CN114727991A - Arylmethylene heterocyclic compounds as Kv1.3 potassium SHAKER channel blockers - Google Patents

Abstract

Compounds of formula I, or pharmaceutically acceptable salts thereof, are described, wherein the substituents are as defined herein. Also described are pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts thereof, and methods of using the compounds or pharmaceutically acceptable salts thereof.

Description

Arylmethylene heterocyclic compounds as Kv1.3 potassium SHAKER channel blockers

This application claims the benefit and priority of U.S. provisional patent application No. 62/911,655, filed on 7/10/2019, the contents of which are incorporated herein by reference in their entirety.

This patent disclosure contains material which is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure, as it appears in the patent and trademark office patent file or records, but otherwise reserves any and all copyright rights whatsoever.

Is incorporated by reference

All documents cited herein are incorporated by reference herein in their entirety.

Technical Field

The invention mainly relates to the field of pharmaceutical science. More particularly, the present invention relates to compounds and compositions useful as pharmaceuticals, such as potassium channel blockers.

Background

Voltage gated Kv1.3 Potassium (K) ⁺) Channels are expressed in lymphocytes (T and B lymphocytes), the central nervous system, and other tissues and regulate a number of physiological processes, such as neurotransmitter release, heart rate, insulin secretion, and neuronal excitability. The Kv1.3 channel can modulate membrane potential, thereby indirectly affecting calcium signaling in human effector memory T cells. Effector memory T cells are mediators of a variety of conditions, including multiple sclerosis, type I diabetes, psoriasis, spondylitis, periodontitis, and rheumatoid arthritis. When activated, effector memory T cells increase expression of kv1.3 channels. In human B cells, naive and early memory B cells express a small number of kv1.3 channels when they are quiescent. In contrast, class-switching memory B cells express a large number of Kv1.3 channels. Further, kv1.3 channels promote calcium homeostasis for T cell receptor-mediated cell activation, gene transcription and proliferation (Panyi, g. et al, 2004,Trends Immunol., 565-569). Blockade of the Kv1.3 channel in effector memory T cells inhibits activities such as calcium signaling, cytokine production (interferon-. gamma., interleukin 2) and elaborationAnd (5) cell proliferation.

Autoimmune diseases are a series of conditions caused by tissue damage resulting from the attack of the body's autoimmune system. Such diseases may affect a single organ, as in multiple sclerosis and type I diabetes, or may involve multiple organs, as in the case of rheumatoid arthritis and systemic lupus erythematosus. Treatment is often palliative, with anti-inflammatory and immunosuppressive drugs being used which may have serious side effects. The need for more effective therapies has led to the search for agents that selectively inhibit effector memory T cell function known to be associated with the etiology of autoimmune diseases. These inhibitors are believed to improve the symptoms of autoimmune diseases without compromising protective immune responses. Effector memory T cells (TEMs) express a large number of kv1.3 channels and rely on these channels for their function. In vivo, kv1.3 channel blockers paralyze TEMs at sites of inflammation and prevent their reactivation in inflamed tissues. Kv1.3 channel blockers do not affect the movement within the lymph nodes of naive and central memory T cells. Inhibition of the function of these cells by selectively blocking the kv1.3 channel offers the potential to effectively treat autoimmune diseases with minimal side effects.

Multiple Sclerosis (MS) is caused by autoimmune damage of the Central Nervous System (CNS). Symptoms include muscle weakness and paralysis, which severely affect the quality of life of the patient. MS progresses rapidly and unpredictably, eventually leading to death. The kv1.3 channel is also highly expressed in autoreactive effector memory T cells from MS patients (Wulff h, et al, 2003,J. Clin. Invest.1703-; rus h, et al, 2005,PNAS, 11094-11099). Animal models of multiple sclerosis have been successfully treated by using blockers of the kv1.3 channel.

Compounds that are selective kv1.3 channel blockers are therefore potential therapeutic agents as immunosuppressive agents or immune system modulators. The Kv1.3 channel is also considered as a therapeutic target for the treatment of obesity and for enhancing peripheral insulin sensitivity in type II diabetic patients. These compounds may also be used to prevent transplant rejection, as well as to treat immune (e.g., autoimmune) and inflammatory disorders.

Tubulointerstitial fibrosis is a progressive connective tissue deposition on the kidney parenchyma leading to deterioration of renal function and participating in the pathology of chronic kidney disease, chronic renal failure, nephritis, and glomerulonephritis, a common cause of end-stage renal failure. Overexpression of kv1.3 channels in lymphocytes can promote their proliferation, leading to chronic inflammation and overstimulation of cellular immunity, which is involved in the underlying pathology of these renal diseases (undersying pathology) and is a contributing factor to the progression of tubulointerstitial fibrosis. Inhibition of lymphocyte kv1.3 channel currents inhibits the proliferation of renal lymphocytes and improves the progression of renal fibrosis (Kazama i, et al, 2015, Mediators Inflamm., 1-12)。

The kv1.3 channel also plays a role in gastrointestinal disorders, including Inflammatory Bowel Disease (IBD) such as Ulcerative Colitis (UC) and crohn's disease. Ulcerative colitis is a chronic IBD characterized by excessive T cell infiltration and cytokine production. Ulcerative colitis impairs quality of life and can lead to life-threatening complications. The high level of kv1.3 channels in CD4 and CD8 positive T cells in inflamed mucosa of patients with UC is associated with the production of pro-inflammatory compounds in active UC. The kv1.3 channel is considered as a marker of disease activity and pharmacological blockade may constitute a new immunosuppressive strategy in UC. Current UC treatment regimens that include corticosteroids, salicylates (salicylates), and anti-TNF-a agents are inadequate for many patients (Hansen l.k. et al, 2014,J. Crohns Colitis, 1378-1391). Crohn's disease is a type of IBD that can affect any part of the gastrointestinal tract. Crohn's disease is believed to be the result of intestinal inflammation caused by T cell driven processes initiated by generally safe bacteria. Thus, Kv1.3 channel inhibition is useful in the treatment of Crohn's disease.

In addition to T cells, kv1.3 channels are also expressed in microglia, where the channels are involved in the production of inflammatory cytokines and nitric oxide and in microglia-mediated neuronal killing. In humans, microglia in the frontal cortex of alzheimer's patients and CD68 of multiple sclerosis brain injury ⁺Strong kv1.3 channel expression was found in the cells. Kv1.3 channel blockers have been shownMay be able to preferentially target deleterious pro-inflammatory microglial function. The Kv1.3 channel is expressed on activated microglia in infarcted rodent and human brain. Higher kv1.3 channel current densities were observed in microglia isolated acutely in the infarcted hemisphere than in the contralateral hemisphere in a stroke mouse model (Chen y.j. et al, 2017,Ann. Clin. Transl. Neurol., 147-161)。

expression of kv1.3 channels is elevated in microglia in human alzheimer's brain, indicating that kv1.3 channels are pathologically relevant microglial targets in alzheimer's disease (Rangaraju s. et al, 2015,J. Alzheimers Dis., 797-808). Soluble a β O enhances microglial kv1.3 channel activity. The Kv1.3 channel is required for A.beta.O-induced pro-inflammatory activation and neurotoxicity of microglia. Kv1.3 channel expression/activity is up-regulated in transgenic Alzheimer's disease animals and human Alzheimer's disease brain. Pharmacological targeting of the microglial Kv1.3 channel may affect hippocampal synaptic plasticity and reduce amyloid deposition in APP/PS1 mice. Therefore, kv1.3 channels may be therapeutic targets for alzheimer's disease.

Kv1.3 channel blockers may also be used to improve the pathology of cardiovascular conditions such as ischemic stroke, in which activated microglia significantly contribute to the secondary expansion of the infarction.

Kv1.3 channel expression is associated with control of proliferation, apoptosis, and cell survival in a variety of cell types. These processes are crucial for cancer progression. In this case, kv1.3 channels located in the inner mitochondrial membrane can interact with the apoptosis regulator Bax (Serrano-albraras, a. et al, 2018,Expert Opin.Ther.Targets, 101-105). Therefore, inhibitors of the kv1.3 channel are useful as anticancer agents.

Many peptide toxins from spiders, scorpions and sea anemones with multiple disulfide bonds are known to block kv1.3 channels. Several selective, potent kv1.3 channel peptide inhibitors have been developed. Synthetic derivatives of actinocongestin (shk) with unnatural amino acids (shk-186) are the most advanced peptide toxins. Shk has demonstrated efficacy in preclinical models and is currently in phase I clinical trials for the treatment of psoriasis. Shk can inhibit the proliferation of TEM cells, thereby ameliorating the pathology of an animal model of multiple sclerosis. Unfortunately, Shk also binds to a closely related subset of Kvi channels found in the CNS and heart. Selective inhibitors of kv1.3 channels are needed to avoid potential cardiac and neurological toxicity. In addition, small peptides such as shk-186 are rapidly cleared from the body after administration, resulting in short circulating half-lives, frequent dosing events. Thus, there is a need to develop long-acting, selective kv1.3 channel inhibitors for the treatment of chronic inflammatory diseases.

Therefore, there is still a need to develop new kv1.3 channel blockers as agents.

Disclosure of Invention

In one aspect, structures having formula I are described

A compound which is a potassium channel blocker, wherein the various substituents are as defined herein. The compounds of formula I described herein can block Kv1.3 potassium (K)⁺) The channels are used to treat various pathologies. Methods of synthesizing these compounds are also described herein. The pharmaceutical compositions described herein and methods of using these compositions are useful for treating conditions in vitro and in vivo. Such compounds, pharmaceutical compositions, and methods of treatment have a number of clinical applications, including as pharmaceutically active agents and methods for treating cancer, immune disorders, Central Nervous System (CNS) disorders, inflammatory disorders, gastrointestinal disorders, metabolic disorders, cardiovascular disorders, renal disorders, or a combination thereof.

In one aspect, compounds of formula I, or pharmaceutically acceptable salts thereof,

；

wherein

Z is OR_a、NR_aR_bOr NR_b(C=O)R_a；

X₁Is H, halogen, CN, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, or halocycloalkyl;

X₂is H, halogen, CN, alkyl, haloalkyl, cycloalkyl or halocycloalkyl;

X₃is H, halogen, fluoroalkyl or alkyl;

or X ₁And X₂Together with the carbon atom to which they are attached form an optionally substituted 6-membered aryl;

or X₂And X₃Together with the carbon atom to which they are attached form an optionally substituted 6-membered aryl group;

R₃is H, halogen or alkyl;

or X₁And R₃Together with the carbon atom to which they are attached form an optionally substituted 6-membered aryl group;

R₁and R₂Each independently is H, alkyl, (CR)₆R₇)_n4OR_a、(CR₆R₇)_n4NR_aR_b、(CR₆R₇)_n4NR_a(C=O)R_b、(CR₆R₇)_n4NR_aSO₂R_bOr (CR)₆R₇)_n4CONR_aR_b(ii) a Or R₁、R₂Together with the carbon atom to which they are attached form a 3-5 membered carbocyclic ring;

R₄is H, alkyl, haloalkyl, optionally substituted cycloalkyl, (CR)₆R₇)_n4OR_c、(CR₆R₇)_n4(C=O)R_c、(C=O)(CR₆R₇)_n4R_c、(CR₆R₇)_n4COOR_c、(CR₆R₇)_n4NR_c(C=O)R_d、(CR₆R₇)_n4(C=O)NR_cR_d、(C=O)(CR₆R₇)_n4NR_cR_d、(CR₆R₇)_n4(C=O)(C=O)NR_cR_d、(C=O)(CR₆R₇)_n4OR_c、(CR₆R₇)_n4SO₂R_c、(CR₆R₇)_n4SO₂NR_cR_dOptionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted-alkyl-aryl, optionally substituted-alkyl-heteroaryl, optionally substituted-alkyl-heterocycle, optionally substituted-alkyl-cycloalkyl or optionally substituted-cycloalkyl-alkyl;

R₅each occurrence of (a) is independently H, alkyl, cycloalkyl or oxo;

or two R₅The groups, together with the carbon atom to which they are attached, form a 3-7 membered optionally substituted saturated carbocyclic ring;

or two R₅The groups are attached to different carbon atoms on the carbocyclic ring and together form a bond or an alkyl chain containing 1-3 carbons;

R₆and R₇Each occurrence of (a) is independently H, alkyl, or cycloalkyl;

R_aAnd R_bEach occurrence of (a) is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl; or R_aAnd R_bTogether with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring containing the nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S;

R_cand R_dEach occurrence of (A) is independently H, alkyl, substituted with 1-4 independently of each other halogen, OR₈Or N (R)₈)₂Substituted alkyl, alkenyl, optionally substituted cycloalkyl, optionally substituted bicycloalkyl, optionally substituted spiroalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted-alkyl-aryl, optionally substituted-alkyl-heteroaryl, optionally substituted-alkyl-heterocycle, optionally substituted-alkyl-cycloalkyl or optionally substituted-cycloalkyl-alkyl; or R_cAnd R_dTogether with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring containing the nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S;

R₈each occurrence of (A) is independently H,Alkyl or optionally substituted heterocycle; or two R₈The groups together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring comprising the nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S;

R₉Is H, alkyl, halogen or (CR)₆R₇)_n4OR_b；

Where valency permits, X₁、X₂、X₃、R₁、R₂、R₃、R₄、R₅、R₆、R₇、R₉、R_a、R_b、R_cAnd R_dThe alkyl, cycloalkyl, spiroalkyl, bicycloalkyl, heterocycle, aryl and heteroaryl groups of (a) are optionally substituted, where applicable, with 1 to 4 substituents each independently selected from alkyl, cycloalkyl, halocycloalkyl, haloalkyl, halogen, CN, - (CH)₂)_0-2OR₈、N(R₈)₂、(C=O)C_1-4Alkyl, (C = O) N (R)₈)₂And oxo;

n, where valency permits₁Each occurrence of (a) is independently an integer from 0 to 3;

n₂and n₃Each occurrence of (a) is independently an integer from 0 to 2; and

n₄each occurrence of (a) is independently an integer from 0 to 3.

In any of the embodiments described herein, n is₂And n₃Each occurrence of (a) is independently an integer from 0 to 1.

In any of the embodiments described herein, a structural motif (motif)

Has the advantages of

、

、

、

Or

The structure of (1).

In any of the embodiments described herein, the structural motif

Has the advantages of

、

Or

The structure of (1).

In any of the embodiments described herein, the structural motif

Has the advantages of

The structure of (1).

In any of the embodiments described herein, R₁And R₂Is H or alkyl.

In any of the embodiments described herein, R₁And R₂At least one occurrence of (CR)₆R₇)_n4OR_a、(CR₆R₇)_n4NR_aR_b、(CR₆R₇)_n4NR_a(C=O)R_b、(CR₆R₇)_n4NR_aSO₂R_bOr (CR)₆R₇)_n4CONR_aR_b。

In any of the embodiments described herein, R ₁And R₂At least one occurrence of is OR_aOr NR_aR_b。

In any of the embodiments described herein, R₁、R₂Together with the carbon atom to which they are attached form a 3-5 membered carbocyclic ring.

In any of the embodiments described herein, R₁And R₂Each independently is H, Me, OH, CH₂OH、NH₂、NHMe、NMe₂、CH₂NH₂、CONH₂、CONHMe₂、CONMe₂、NH(C=O)Me、NMe(C=O)Me、

、

、

、

、

Or

。

In any of the embodiments described herein, R₄Is H, alkyl, haloalkyl or cycloalkyl.

In any of the embodiments described herein, R₄Is H, Me or fluoroethyl.

In any of the embodiments described herein, R₄Is (CR)₆R₇)_n4OR_c、(CR₆R₇)_n4COR_c、(C=O)(CR₆R₇)_n4R_c、(CR₆R₇)_n4COOR_c、(CR₆R₇)_n4NR_c(C=O)R_d、(CR₆R₇)_n4(C=O)NR_cR_d、(CR₆R₇)_n4(C=O)(C=O)NR_cR_d、(C=O)(CR₆R₇)_n4OR_c、(CR₆R₇)_n4SO₂R_cOr (CR)₆R₇)_n4SO₂NR_cR_d。

In any of the embodiments described herein, R₄Is (CR)₆R₇)₂OR_c、(C=O)R_c、(C=O)(CR₆R₇)_1-2R_c、COOR_c、(CR₆R₇)_1-2NR_c(C=O)R_d、(C=O)NR_cR_d、(CR₆R₇)_n4(C=O)(C=O)NR_cR_d、(C=O)(CR₆R₇)_1-2OR_c、SO₂R_cOr SO₂NR_cR_d。

In any of the embodiments described herein, R₄Is (CH)₂)₂OH、(CH₂)₂OMe、(C=O)H、(C=O)Me、(C=O)CH₂OH、(C=O)CH₂OMe, (C = O) Et, (C = O) Ph, (C = O) isopropyl, (C = O) NH₂、(C=O)NHMe、(C=O)NMe₂、(C=O)CH₂NH₂、(C=O)CH₂NHMe、(C=O)CH(OH)CH₂OH、(C=O)CH(OMe)CH₂OH、(C=O)CH(OH)CH₂OMe、(C=O)(C=O)NMe₂、(C=O)OMe、SO₂Me、SO₂Et、SO₂CH₂OH、SO₂CH₂OMe、SO₂NH₂、SO₂NHMe or SO₂NMe₂。

In any of the embodiments described herein, R₄Is (C = O) R_c、(C=O)(CR₆R₇)_1-2R_c、(C=O)(CR₆R₇)_{1- 2}OR_cOr SO₂R_c(ii) a And it isIn R_cSelected from H, alkyl, by being each independently selected from halogen, OR₈And N (R)₈)₂Optionally substituted alkyl, alkenyl, optionally substituted cycloalkyl, optionally substituted bicycloalkyl, optionally substituted spiroalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted-alkyl-aryl, optionally substituted-alkyl-heteroaryl, optionally substituted-alkyl-heterocycle, optionally substituted-alkyl-cycloalkyl, and optionally substituted-cycloalkyl-alkyl.

In any of the embodiments described herein, R_cOr R_dIs H, Me, Et,

。

In any of the embodiments described herein, R_cOr R_dIs a heterocycle selected from:

wherein the heterocycle is optionally substituted, where valence permits, with one or more cyano, cycloalkyl, fluoroalkyl, fluorocycloalkyl, halogen, OH, NH₂Oxo or (C = O) C_1-4Alkyl substitution.

In any of the embodiments described herein, R, where permitted by valence_cAre each optionally substituted by 1 to 4Cycloalkyl, spiroalkyl or bicycloalkyl substituted with substituents each independently selected from alkyl, halogen, CN, - (CH)₂)_0-2OR₈、N(R₈)₂、(C=O)N(R₈)₂And oxo.

In any of the embodiments described herein, R, where permitted by valence_cAre each optionally substituted with 1 to 4 substituents

Each of said substituents being independently selected from alkyl, halogen, CN, - (CH)₂)_0-2OR₈、N(R₈)₂、(C=O)N(R₈)₂And oxo.

In any of the embodiments described herein, R₄Is optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted-alkyl-aryl, optionally substituted-alkyl-heteroaryl, optionally substituted-alkyl-heterocycle, optionally substituted cycloalkyl, optionally substituted-alkyl-cycloalkyl or optionally substituted-cycloalkyl-alkyl.

In any of the embodiments described herein, R₄Is a heterocycle selected from:

wherein the heterocycle is optionally substituted, as valence permits, with one or more cyano groupsCycloalkyl, fluoroalkyl, fluorocycloalkyl, halogen, OH, NH₂Oxo or (C = O) C_1-4Alkyl substitution.

In any of the embodiments described herein, R, where permitted by valence₄Is cycloalkyl optionally substituted with 1-4 substituents each independently selected from alkyl, halogen, CN, - (CH)₂)_0-2OR₈、N(R₈)₂、(C=O)N(R₈)₂And oxo.

In any of the embodiments described herein, R, where permitted by valence₄Are each optionally substituted by 1 to 4 substituents

Each of said substituents being independently selected from alkyl, halogen, CN, - (CH)₂)_0-2OR₈、N(R₈)₂、(C=O)N(R₈)₂And oxo.

In any of the embodiments described herein, R₄The method comprises the following steps:

or a tautomer thereof.

In any of the embodiments described herein, R₅At leastOne occurrence is H, alkyl or cycloalkyl.

In any of the embodiments described herein, R₅Is oxo.

In any of the embodiments described herein, two R are₅The groups are attached to different carbon atoms on the carbocyclic ring and together form a bond or an alkyl chain containing 1-3 carbons.

In any of the embodiments described herein, two R are₅The groups together with the carbon atoms to which they are attached form a 3-7 membered optionally substituted saturated carbocyclic ring.

In any of the embodiments described herein, R_aAnd R_bIs independently H, alkyl, cycloalkyl, saturated heterocycle, aryl or heteroaryl.

In any of the embodiments described herein, R_aAnd R_bTogether with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring containing the nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S.

In any of the embodiments described herein, R₆And R₇Each occurrence of (a) is independently H or alkyl.

In any of the embodiments described herein, R₉Is H, alkyl or halogen.

In any of the embodiments described herein, R₉Is (CR)₆R₇)_n4OR_b。

In any of the embodiments described herein, R₉Is H, F or OH.

In any of the embodiments described herein, Z is OR_a、NR_aR_bOr NR_b(C=O)R_a。

In any of the embodiments described herein, Z is OH, OMe, NH₂NHMe or NMe₂。

In any of the embodiments described herein, Z is OH.

In any of the embodiments described herein, X₁Is H, halogen, fluoroalkyl or alkyl.

In any of the embodiments described herein, X ₁Is H, F, Cl, Br, Me, CF₃Or CF₂Cl。

In any of the embodiments described herein, X₁Is Me or Cl.

In any of the embodiments described herein, X₂Is H, halogen, fluoroalkyl or alkyl.

In any of the embodiments described herein, X₂Is H, F, Cl, Br, Me, CF₃Or CF₂Cl。

In any of the embodiments described herein, X₂Is Cl.

In any of the embodiments described herein, X₃Is H, F, Cl, Br, fluoroalkyl or alkyl.

In any of the embodiments described herein, X₃Is H, F, Cl or CF₃。

In any of the embodiments described herein, a moiety

Having each of the radicals represented by R₃Substituted by

The structure of (1).

In any of the embodiments described herein, R₃Is H or alkyl.

In any of the embodiments described herein, R₃Is a halogen.

In any of the embodiments described herein, the compound has the structure of formula II,

；

R_3’each occurrence of (a) is independently H, halogen, or alkyl; and

n₆is an integer of 0 to 2.

In any of the embodiments described herein, R_3’Is H or alkyl.

In any of the embodiments described herein, R_3’Is halogen.

In any of the embodiments described herein, R ₈Is H, alkyl or an optionally substituted heterocycle.

In any of the embodiments described herein, R₈Is H, Me, Et, Pr, Bu or a heterocycle selected from:

(ii) a Wherein the heterocycle is optionally substituted, where valence permits, with one or more cyano, cycloalkyl, fluoroalkyl, fluorocycloalkyl, halogen, OH, NH₂Oxo or (C = O) C_1-4Alkyl substitution.

In any of the embodiments described herein, two R are₈The groups, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclic ring comprising the nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S.

In any of the embodiments described herein, n is₁Is 0, 1, 2 or 3.

In any of the embodiments described herein, n is₄Is 0, 1 or 2.

In any of the embodiments described herein, R_cOr R_dIs independently H, alkyl, is independently selected from halogen, OR₈And N (R)₈)₂Alkyl, alkenyl, cycloalkyl optionally substituted, bicycloalkyl optionally substituted, spiroalkyl optionally substituted, substituted or unsubstitutedSubstituted saturated heterocyclic ring, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted-alkyl-aryl, optionally substituted-alkyl-heteroaryl, optionally substituted-alkyl-heterocyclic ring, optionally substituted-alkyl-cycloalkyl or optionally substituted-cycloalkyl-alkyl.

In any of the embodiments described herein, R_cAnd R_dTogether with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring containing the nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S.

In any of the embodiments described herein, R_cOr R_dIs independently H, Me, Et,

In any of the embodiments described herein, R_cOr R_dIs independently a heterocycle selected from:

wherein the heterocycle is optionally substituted, where valence permits, with one or more cyano, cycloalkyl, fluoroalkyl, fluorocycloalkyl, halogen, OH, NH₂Oxo or (C = O) C_1-4Alkyl substitution.

In any of the embodiments described herein, the valency allowsIn many cases, R_cOr R_dIs cycloalkyl, spiroalkyl or bicycloalkyl, each optionally substituted with 1-4 substituents, each independently selected from alkyl, halogen, CN, - (CH)₂)_0-2OR₈、N(R₈)₂、(C=O)N(R₈)₂And oxo.

In any of the embodiments described herein, R, where permitted by valence_cOr R_dIndependently of each other being optionally substituted by 1 to 4 substituents

Each of said substituents being independently selected from alkyl, halogen, CN, - (CH) ₂)_0-2OR₈、N(R₈)₂、(C=O)N(R₈)₂And oxo.

In any of the embodiments described herein, the compound is selected from compounds 1-338 of table 1.

In another aspect, a pharmaceutical composition is described comprising at least one compound according to any one of the embodiments described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

In yet another aspect, a method of treating a condition in a mammalian species in need thereof is described, comprising administering to the mammalian species a therapeutically effective amount of at least one compound of any of the embodiments described herein, or a pharmaceutically acceptable salt thereof, wherein the condition is selected from the group consisting of cancer, an immune disorder, a Central Nervous System (CNS) disorder, an inflammatory disorder, a gastrointestinal disorder, a metabolic disorder, a cardiovascular disorder, and a renal disorder.

In any of the embodiments described herein, the immune disorder is transplant rejection or an autoimmune disease.

In any of the embodiments described herein, the autoimmune disease is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes.

In any of the embodiments described herein, the Central Nervous System (CNS) disorder is alzheimer's disease.

In any of the embodiments described herein, the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontitis, or an inflammatory neuropathy.

In any of the embodiments described herein, the gastrointestinal disorder is inflammatory bowel disease.

In any of the embodiments described herein, the metabolic disorder is obesity or type II diabetes.

In any of the embodiments described herein, the cardiovascular disorder is ischemic stroke.

In any of the embodiments described herein, the renal disease is chronic kidney disease, nephritis, or chronic renal failure.

In any of the embodiments described herein, the condition is selected from the group consisting of cancer, transplant rejection, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes, alzheimer's disease, inflammatory skin conditions, inflammatory neuropathy, psoriasis, spondylitis, periodontitis, crohn's disease, ulcerative colitis, obesity, type II diabetes, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and combinations thereof.

In any of the embodiments described herein, the mammalian species is human.

In yet another aspect, a method of blocking kv1.3 potassium channels in a mammalian species in need thereof is described comprising administering to the mammalian species a therapeutically effective amount of at least one compound of any of the embodiments described herein, or a pharmaceutically acceptable salt thereof.

In any of the embodiments described herein, the mammalian species is human.

Any embodiment disclosed herein may be combined with any other embodiment disclosed herein as appropriate. Combinations of any embodiment disclosed herein with any other embodiment disclosed herein are expressly contemplated. In particular, the selection of one or more embodiments of one substituent may be combined appropriately with the selection of one or more particular embodiments of any other substituent. Such combinations may be made in any one or more embodiments of the uses described herein or in any of the formulations described herein.

Detailed Description

Definition of

The following are definitions of terms used in this specification. Unless otherwise indicated, the initial definitions provided herein for a group or term apply to that group or term throughout this specification, either alone or as part of another group. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

The term "alkyl" and "alk" refers to a straight or branched chain alkane (hydrocarbon) group containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Exemplary "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutylpentyl, hexyl, isohexyl, heptyl, 4-dimethylpentyl, octyl, 2, 4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. Term "(C) _1-C₄) Alkyl "means a straight or branched chain alkane (hydrocarbon) group containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl. "substituted alkyl" refers to alkyl substituted at any available point of attachment with one or more substituents, preferably 1-4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g. single halogen substituent or multiple halogen substituents, in the latter case forming a group, e.g. CF)₃Or with CCl₃Alkyl group of (i), cyano group, nitro group, oxo group (i.e., = O), CF₃、OCF₃Cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR_a、SR_a、S(=O)R_e、S(=O)₂R_e、P(=O)₂R_e、S(=O)₂OR_e、P(=O)₂OR_e、NR_bR_c、NR_bS(=O)₂R_e、NR_bP(=O)₂R_e、S(=O)₂NR_bR_c、P(=O)₂NR_bR_c、C(=O)OR_d、C(=O)R_a、C(=O)NR_bR_c、OC(=O)R_a、OC(=O)NR_bR_c、NR_bC(=O)OR_e、NR_dC(=O)NR_bR_c、NR_dS(=O)₂NR_bR_c、NR_dP(=O)₂NR_bR_c、NR_bC(=O)R_aOr NR_bP(=O)₂R_eWherein R is_aEach occurrence of (a) is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; r_b、R_cAnd R_dEach occurrence of (A) is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R_bAnd R_c Optionally forming a heterocyclic ring together with the N to which they are bonded; and R is_eEach occurrence of (a) is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. In some embodiments, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl may themselves be optionally substituted.

The term "alkenyl" refers to a straight or branched hydrocarbon group containing 2-12 carbon atoms and at least one carbon-carbon double bond. Exemplary such groups include vinyl or allyl. The term "C₂-C₆Alkenyl "means a straight or branched hydrocarbon group containing 2 to 6 carbon atoms and at least one carbon-carbon double bond, such as ethenyl, propenyl, 2-propenyl, (ii) ethenylE) -but-2-enyl, ((iii))Z) But-2-enyl, 2-methyl(s) (iii)E) But-2-enyl, 2-methyl(s) (iii)Z) -but-2-enyl, 2, 3-methyl-but-2-enyl, (Z) Pent-2-enyl group, ((iii))E) Pent-1-enyl group, ((iii))Z) -hex-1-enyl, (E) Pent-2-enyl group, ((iii))Z) -hex-2-enyl, (E) -hex-2-enyl, (Z) -hex-1-enyl, (E) -hex-1-enyl, (Z) -hex-3-enyl, (E) -hex-3-enylAnd (a) and (b)E) -hex-1, 3-dienyl. "substituted alkenyl" refers to alkenyl substituted at any available point of attachment with one or more substituents, preferably 1-4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen, alkyl, haloalkyl (i.e. an alkyl group bearing a single halogen substituent or multiple halogen substituents, e.g. CF)₃Or CCl₃) Cyano, nitro, oxo (i.e., = O), CF₃、OCF₃Cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR _a、SR_a、S(=O)R_e、S(=O)₂R_e、P(=O)₂R_e、S(=O)₂OR_e、P(=O)₂OR_e、NR_bR_c、NR_bS(=O)₂R_e、NR_bP(=O)₂R_e、S(=O)₂NR_bR_c、P(=O)₂NR_bR_c、C(=O)OR_d、C(=O)R_a、C(=O)NR_bR_c、OC(=O)R_a、OC(=O)NR_bR_c、NR_bC(=O)OR_e、NR_dC(=O)NR_bR_c、NR_dS(=O)₂NR_bR_c、NR_dP(=O)₂NR_bR_c、NR_bC(=O)R_aOr NR_bP(=O)₂R_eWherein R is_aEach occurrence of (a) is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; r_b、R_cAnd R_dEach occurrence of (A) is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R_bAnd R_cOptionally forming a heterocyclic ring together with the N to which they are bonded; and R is_eEach occurrence of (a) is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be optionally substituted.

The term "alkynyl" refers to a straight or branched hydrocarbon group containing 2-12 carbon atoms and at least one carbon-carbon triple bond. Exemplary such groups include ethynyl. The term "C₂-C₆Alkynyl "means a straight or branched chain hydrocarbon group containing 2 to 6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl. "substituted alkynyl" refers to alkynyl groups substituted at any available point of attachment with one or more substituents, preferably 1-4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g. single halogen substituent or multiple halogen substituents, in the latter case forming a group, e.g. CF) ₃Or with CCl₃Alkyl group of (i), cyano group, nitro group, oxo group (i.e., = O), CF₃、OCF₃Cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR_a、SR_a、S(=O)R_e、S(=O)₂R_e、P(=O)₂R_e、S(=O)₂OR_e、P(=O)₂OR_e、NR_bR_c、NR_bS(=O)₂R_e、NR_bP(=O)₂R_e、S(=O)₂NR_bR_c、P(=O)₂NR_bR_c、C(=O)OR_d、C(=O)R_a、C(=O)NR_bR_c、OC(=O)R_a、OC(=O)NR_bR_c、NR_bC(=O)OR_e、NR_dC(=O)NR_bR_c、NR_dS(=O)₂NR_bR_c、NR_dP(=O)₂NR_bR_c、NR_bC(=O)R_aOr NR_bP(=O)₂R_eWherein R is_aEach occurrence of (a) is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; r_b、R_cAnd R_dEach occurrence of (A) is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R_bAnd R_c Optionally forming a heterocyclic ring together with the N to which they are bonded; and R is_eEach occurrence of (a) is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituentsMay itself be optionally substituted.

The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. "C₃-C₇Cycloalkyl "means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. "substituted cycloalkyl" refers to cycloalkyl substituted at any available point of attachment with one or more substituents, preferably 1-4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g. single halogen substituent or multiple halogen substituents, in the latter case forming a group, e.g. CF) ₃Or with CCl₃Alkyl group of (i), cyano, nitro, oxo (i.e., = O), CF₃OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR_a、SR_a、S(=O)R_e、S(=O)₂R_e、P(=O)₂R_e、S(=O)₂OR_e、P(=O)₂OR_e、NR_bR_c、NR_bS(=O)₂R_e、NR_bP(=O)₂R_e、S(=O)₂NR_bR_c、P(=O)₂NR_bR_c、C(=O)OR_d、C(=O)R_a、C(=O)NR_bR_c、OC(=O)R_a、OC(=O)NR_bR_c、NR_bC(=O)OR_e、NR_dC(=O)NR_bR_c、NR_dS(=O)₂NR_bR_c、NR_dP(=O)₂NR_bR_c、NR_bC(=O)R_aOr NR_bP(=O)₂R_eWherein R is_aEach occurrence of (a) is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; r_b、R_cAnd R_dEach occurrence of (A) is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R_bAnd R_c Optionally forming a heterocyclic ring together with the N to which they are bonded; and R is_eEach occurrence of (a) is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substitutionsThe radicals themselves may optionally be substituted. Exemplary substituents also include: spiro-linked or fused cyclic substituents, especially spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle or fused aryl, wherein the above cycloalkyl, cycloalkenyl, heterocycle and aryl substituents may themselves be optionally substituted.

The term "cycloalkenyl" refers to partially unsaturated cyclic hydrocarbon groups containing from 1 to 4 rings and from 3 to 8 carbons per ring. Exemplary such groups include: cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like. "substituted cycloalkenyl" refers to cycloalkenyl substituted with one or more substituents, preferably 1-4 substituents, at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g. single halogen substituent or multiple halogen substituents, in the latter case forming a group, e.g. CF) ₃Or with CCl₃Alkyl group of (i), cyano group, nitro group, oxo group (i.e., = O), CF₃、OCF₃Cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR_a、SR_a、S(=O)R_e、S(=O)₂R_e、P(=O)₂R_e、S(=O)₂OR_e、P(=O)₂OR_e、NR_bR_c、NR_bS(=O)₂R_e、NR_bP(=O)₂R_e、S(=O)₂NR_bR_c、P(=O)₂NR_bR_c、C(=O)OR_d、C(=O)R_a、C(=O)NR_bR_c、OC(=O)R_a、OC(=O)NR_bR_c、NR_bC(=O)OR_e、NR_dC(=O)NR_bR_c、NR_dS(=O)₂NR_bR_c、NR_dP(=O)₂NR_bR_c、NR_bC(=O)R_aOr NR_bP(=O)₂R_eWherein R is_aEach occurrence of (a) is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; r_b、R_cAnd R_dEach occurrence of (A) is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R_bAnd R_c Optionally forming a heterocyclic ring together with the N to which they are bonded; and R is_eEach occurrence of (a) is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include: spiro-linked or fused cyclic substituents, especially spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, wherein the above cycloalkyl, cycloalkenyl, heterocycle and aryl substituents may themselves be optionally substituted.

The term "aryl" refers to a cyclic aromatic hydrocarbon radical having 1-5 aromatic rings, especially a monocyclic or bicyclic radical, such as phenyl, biphenyl or naphthyl. When containing two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl groups can be linked at a single point (e.g., biphenyl), or fused (e.g., naphthyl, phenanthrenyl, etc.). The term "fused aromatic ring" refers to a molecular structure having two or more aromatic rings in which two adjacent aromatic rings have two carbon atoms in common. "substituted aryl" refers to aryl substituted at any available point of attachment with one or more substituents, preferably 1-4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g. single halogen substituent or multiple halogen substituents, in the latter case forming a group, e.g. CF) ₃Or with CCl₃Alkyl group of (i), cyano, nitro, oxo (i.e., = O), CF₃、OCF₃Cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR_a、SR_a、S(=O)R_e、S(=O)₂R_e、P(=O)₂R_e、S(=O)₂OR_e、P(=O)₂OR_e、NR_bR_c、NR_bS(=O)₂R_e、NR_bP(=O)₂R_e、S(=O)₂NR_bR_c、P(=O)₂NR_bR_c、C(=O)OR_d、C(=O)R_a、C(=O)NR_bR_c、OC(=O)R_a、OC(=O)NR_bR_c、NR_bC(=O)OR_e、NR_dC(=O)NR_bR_c、NR_dS(=O)₂NR_bR_c、NR_dP(=O)₂NR_bR_c、NR_bC(=O)R_aOr NR_bP(=O)₂R_eWherein R is_aIndependently for each occurrence is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl; r is_b、R_cAnd R_dEach occurrence of (A) is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R_bAnd R_c Optionally forming a heterocyclic ring together with the N to which they are bonded; and R is_eEach occurrence of (a) is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include: fused cyclic groups, in particular fused cycloalkyl, fused cycloalkenyl, fused heterocycle or fused aryl, wherein the above cycloalkyl, cycloalkenyl, heterocycle and aryl substituents may themselves be optionally substituted.

The term "biaryl" refers to two aryl groups connected by a single bond. The term "biheteroaryl" refers to two heteroaryl groups connected by a single bond. Similarly, the term "heteroaryl-aryl" refers to heteroaryl and aryl groups connected by a single bond, and the term "aryl-heteroaryl" refers to aryl and heteroaryl groups connected by a single bond. In certain embodiments, the number of ring atoms in the heteroaryl and/or aryl ring is used to designate the size of the aryl or heteroaryl ring in the substituent. For example, 5, 6-heteroaryl-aryl refers to a substituent in which a 5-membered heteroaryl is attached to a 6-membered aryl. Other combinations and ring sizes may be similarly specified.

The term "carbocycle" or "carbon cycle" refers to a fully or partially saturated cyclic hydrocarbon radical containing 1 to 4 rings and 3 to 8 carbons per ring, or a cyclic aromatic hydrocarbon radical having 1 to 5 aromatic rings, especially a monocyclic or bicyclic radical such as phenyl, biphenyl or naphthyl. The term "carbocycle" encompasses cycloalkyl, cycloalkenyl, cycloalkynyl and aryl groups as defined above. The term "substituted carbocyclic" refers to a carbocyclic or carbocyclic group substituted at any available point of attachment with one or more substituents, preferably 1-4 substituents. Exemplary substituents include, but are not limited to, those described above for substituted cycloalkyl, substituted cycloalkenyl, substituted cycloalkynyl, and substituted aryl. Exemplary substituents also include: spiro-linked or fused cyclic substituents at any available point or points of attachment, especially spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, wherein the cycloalkyl, cycloalkenyl, heterocycle and aryl substituents described above may themselves be optionally substituted.

The term "heterocycle" ("heterocyclic" and "heterocyclic") refers to a fully saturated or partially or fully unsaturated, including aromatic (i.e., "heteroaryl") cyclic group (e.g., a 3-7 membered monocyclic, 7-11 membered bicyclic, or 8-16 membered tricyclic ring system) having at least one heteroatom in at least one carbon-containing ring. Each ring of a heterocyclyl group may be independently saturated or partially or fully unsaturated. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. (the term "heteroarylonium" refers to a heteroaryl group that carries a quaternary nitrogen atom and thus a positive charge.) the heterocyclic group may be attached to the rest of the molecule at any heteroatom or carbon atom of a ring or ring system. Exemplary monocyclic heterocyclic groups include: azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2- Oxo-azapine, hexahydrodiazepinyl, 4-piperidonyl (piperidonyl), pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl sulfoxide (thiomorpholinyl sulfoxide), morpholinyl sulfone (thiomorpholinyl sulfone), 1, 3-dioxolane, tetrahydro-1, 1-dioxothienyl, and the like. Exemplary bicyclic heterocyclic groups include: indolyl, indolinyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzooxadiazolyl, benzothienyl, benzo [2 ], [d][1,3]Dioxolyl, dihydro-2H-benzo [ alpha ], [ alpha ] orb][1,4]Oxazines, 2, 3-dihydrobenzo [ b ]][1,4]Dioxinyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, benzofurazanyl, dihydrobenzo [ alpha ], [ beta ] -a ] and [ beta ], [ beta ] -n ] and [ beta ] -n ] ad]Oxazole, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridinyl, furopyridinyl (e.g. furo [2,3-c ]]Pyridyl, furo [3,2-b ]]Pyridyl radical]Or furo [2,3-b ]]Pyridyl), dihydroisoindolyl, dihydroquinazolinyl (e.g., 3, 4-dihydro-4-oxo-quinazolinyl), triazinyl azepin, tetrahydroquinolinyl, and the like. Exemplary tricyclic heterocyclic groups include: carbazolyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

"substituted heterocycle" and "substituted heterocyclic" (e.g., "substituted heteroaryl") refer to a heterocycle or heterocyclic group substituted at any available point of attachment with one or more substituents, preferably 1-4 substituents. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g. single halogen substituent or multiple halogen substituents, in the latter case forming a group, e.g. CF)₃Or with CCl₃Alkyl group of (i), cyano group, nitro group, oxo group (i.e., = O), CF₃、OCF₃Cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR_a、SR_a、S(=O)R_e、S(=O)₂R_e、P(=O)₂R_e、S(=O)₂OR_e、P(=O)₂OR_e、NR_bR_c、NR_bS(=O)₂R_e、NR_bP(=O)₂R_e、S(=O)₂NR_bR_c、P(=O)₂NR_bR_c、C(=O)OR_d、C(=O)R_a、C(=O)NR_bR_c、OC(=O)R_a、OC(=O)NR_bR_c、NR_bC(=O)OR_e、NR_dC(=O)NR_bR_c、NR_dS(=O)₂NR_bR_c、NR_dP(=O)₂NR_bR_c、NR_bC(=O)R_aOr NR_bP(=O)₂R_eWherein R is_aEach occurrence of (a) is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; r_b、R_cAnd R_dEach occurrence of (A) is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R_bAnd R_c Optionally forming a heterocyclic ring together with the N to which they are bonded; and R is_eEach occurrence of (a) is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be optionally substituted. Exemplary substituents also include: spiro-linked or fused cyclic substituents at any available point or points of attachment, especially spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, wherein the above cycloalkyl, cycloalkenyl, heterocycle and aryl substituents may themselves be optionally substituted.

The term "oxo" refers to

A substituent which may be attached to a carbon ring atom on a carbocyclic or heterocyclic ring. When an oxo substituent is attached to a carbocyclic atom on an aromatic group (e.g., aryl or heteroaryl), the bonds on the aromatic ring can be rearranged to meet valence requirements. For example, a pyridine having a 2-oxo substituent may have the structure

It also includes tautomers thereof

。

The term "alkylamino" refers to a group having the structure-NHR ', wherein R' is hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, as defined herein. Examples of alkylamino groups include, but are not limited to: methylamino, ethylamino, n-propylamino, isopropylamino, cyclopropylamino, n-butylamino, t-butylamino, neopentylamino, n-pentylamino, hexylamino, cyclohexylamino and the like.

The term "dialkylamino" refers to a group having the structure-NRR ', wherein R and R' are each independently alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic, as defined herein. R and R' may be the same or different in the dialkylamino moiety. Examples of dialkylamino groups include, but are not limited to: dimethylamino, methylethylamino, diethylamino, methylpropylamino, di (n-propyl) amino, di (isopropyl) amino, di (cyclopropyl) amino, di (n-butyl) amino, di (tert-butyl) amino, di (neopentyl) amino, di (n-pentyl) amino, di (hexyl) amino, di (cyclohexyl) amino and the like. In certain embodiments, R and R' are joined to form a cyclic structure. The resulting cyclic structure may be aromatic or non-aromatic. Examples of resulting cyclic structures include, but are not limited to: aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, 1,3, 4-triazinyl (triazinolyl), and tetrazolyl.

The term "halogen" or "halo" refers to chlorine, bromine, fluorine or iodine.

The term "substituted" refers to a molecule, molecular moiety, or substituent (e.g., alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aryl or any other group disclosed herein) wherein the valence permits it to be by oneEmbodiments in which one or more substituents, preferably 1 to 6 substituents, are substituted at any available point of attachment. Exemplary substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g. single halogen substituent or multiple halogen substituents, in the latter case forming a group, e.g. CF)₃Or with CCl₃Alkyl group of (i), cyano group, nitro group, oxo group (i.e., = O), CF₃、OCF₃Alkyl, haloalkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR_a、SR_a、S(=O)R_e、S(=O)₂R_e、P(=O)₂R_e、S(=O)₂OR_e、P(=O)₂OR_e、NR_bR_c、NR_bS(=O)₂R_e、NR_bP(=O)₂R_e、S(=O)₂NR_bR_c、P(=O)₂NR_bR_c、C(=O)OR_d、C(=O)R_a、C(=O)NR_bR_c、OC(=O)R_a、OC(=O)NR_bR_c、NR_bC(=O)OR_e、NR_dC(=O)NR_bR_c、NR_dS(=O)₂NR_bR_c、NR_dP(=O)₂NR_bR_c、NR_bC(=O)R_aOr NR_bP(=O)₂R_eWherein R is_aEach occurrence of (a) is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; r_b、R_cAnd R_dEach occurrence of (A) is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R_bAnd R_c Optionally forming a heterocyclic ring together with the N to which they are bonded; and R is_eEach occurrence of (a) is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. In the above exemplary substituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle and aryl may themselves be optionally substituted. The term "optionally substituted" refers to where a molecule, molecular moiety, or substituent (e.g., alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle) is present Or aryl or any other group disclosed herein) may or may not be substituted with one or more substituents described above.

Unless otherwise indicated, it is assumed that any heteroatom having an unsaturated valence has a hydrogen atom sufficient to satisfy the compound.

The compounds of the present invention may form salts, which are also within the scope of the present invention. Unless otherwise indicated, reference to a compound of the invention is to be understood as including reference to a salt thereof. As used herein, the term "salt" means an acidic and/or basic salt formed with inorganic and/or organic acids and bases. In addition, when a compound of the present invention comprises a basic moiety (such as, but not limited to, a pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid), zwitterions ("inner salts") may be formed and are included within the scope of "salts" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in isolation or purification steps that may be employed in the preparation. Salts of the compounds of the present invention may be formed, for example, by: the compounds described herein are reacted with an amount of an acid or base (e.g., equivalent weight) in a medium such as a salt precipitate or in an aqueous medium, followed by lyophilization.

Compounds of the invention containing a basic moiety such as, but not limited to, an amine or pyridine or imidazole ring may form salts with various organic and inorganic acids. Exemplary acid addition salts include: acetates (such as those formed with acetic acid or trihaloacetic acid such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptonates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonates), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonates), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionates), phosphates, salts of acetic acid, Picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates, tartrates, thiocyanates, tosylates such as tosylates, undecanoates, and the like.

Compounds of the invention containing an acidic moiety (such as, but not limited to, a phenol or a carboxylic acid) can form salts with a variety of organic and inorganic bases. Exemplary basic salts include: an ammonium salt; alkali metal salts (such as sodium, lithium and potassium salts); alkaline earth metal salts (e.g., calcium and magnesium salts); salts with organic bases (e.g., organic amines) such as benzathine, dicyclohexylamine, hydrabamine (formed with N, N-bis (dehydroabietyl) ethylenediamine), N-methyl-D-glucamine, N-methyl-D-aminoacetamide (N-methyl-D-glycinamide), tert-butylamine; and salts with amino acids (e.g., arginine, lysine), and the like. Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and the like.

Prodrugs and solvates of the compounds of the present invention are also contemplated herein. As used herein, the term "prodrug" refers to a compound that undergoes chemical conversion by metabolic or chemical processes to yield a compound of the invention, or a salt and/or solvate thereof, upon administration to a subject. Solvates of the compounds of the invention include, for example, hydrates.

The compounds of the invention and salts or solvates thereof may exist in their tautomeric form (e.g., as an amide or imino ether). All such tautomers are considered part of the present invention. As used herein, any indicated structure of a compound includes tautomers thereof.

All stereoisomers of the compounds of the invention, including enantiomers and diastereomers (e.g., those that may exist due to asymmetric carbons on the various substituents), are considered to be within the scope of the invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers (e.g. as pure or substantially pure optical isomers with a particular activity), or may, for example, be as racemates or in admixture with all other or other selected stereoisomers. The chiral centers of the invention may have the S or R configuration as defined in the International Union of Pure and Applied Chemistry (IUPAC)1974 recommendation. Racemates can be resolved by physical methods such as fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates by any suitable method, including but not limited to conventional methods, such as salt formation with an optically active acid, followed by crystallization.

After preparation of the compounds of the present invention, they are preferably isolated and purified to obtain a composition containing equal to or greater than 90%, e.g., equal to or greater than 95%, equal to or greater than 99%, by weight, of the compound (the "substantially pure" compound), which is then used or formulated as described herein. Such "substantially pure" compounds of the invention are also considered to be part of the invention.

All configurational isomers of the compounds of the present invention, whether in admixture or in pure or substantially pure form, are contemplated. The definition of the compounds of the present invention includes cis (Z) and trans (E) alkene isomers, as well as cis and trans isomers of cyclic hydrocarbons or heterocycles.

Throughout the specification, groups and substituents thereof may be selected to provide stable moieties and compounds.

Definitions of specific functional groups and chemical terms are described in more detail herein. For the purposes of the present invention, the chemical elements are identified according to the CAS version of the periodic Table of the elements, Handbook of Chemistry and Physics, 75 th edition, internal cover, the specific functional groups being generally defined as described therein. Furthermore, the general principles of Organic Chemistry, as well as specific functional moieties and reactivity, are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito (1999), the entire contents of which are incorporated herein by reference.

Certain compounds of the present invention may exist as specific geometric or stereoisomers. The present invention contemplates that all such compounds, including cis and trans isomers, R-and S-enantiomers, diastereomers, (d) -isomers, (l) -isomers, racemic and other mixtures thereof, fall within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included in the present invention.

According to the invention, isomer mixtures containing any of the various isomer ratios can be used. For example, when only two isomers are combined, the invention encompasses all mixtures containing ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 isomers. One of ordinary skill in the art will readily appreciate that similar ratios are contemplated for more complex isomer mixtures.

The invention also includes isotopically-labeled compounds, which are identical to those disclosed herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example each ²H、³H、¹³C、¹¹C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F. And³⁶and (4) Cl. Compounds of the present invention containing the aforementioned isotopes and/or other isotopes of other atoms, or enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, are within the scope of the present invention. Certain isotopically-labeled compounds of the present invention are for example those into which radioactive isotopes such as³H and¹⁴those of C are useful in drug and/or substrate tissue distribution assays. Tritium generation namely³H. And carbon-14 is¹⁴The C isotope is particularly preferred because of its ease of preparation and detection. Further, the method can be used for preparing a novel liquid crystal displayWith heavier isotopes such as deuterium²H substitution may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in some circumstances. Isotopically labeled compounds can generally be prepared by carrying out the procedures disclosed in the schemes and/or in the examples below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

For example, if a particular enantiomer of a compound of the invention is desired, it may be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group such as an amino group or an acidic functional group such as a carboxyl group, diastereomeric salts are formed with a suitable optically active acid or base, and the diastereomers thus formed are then resolved by fractional crystallization or chromatographic methods well known in the art, followed by recovery of the pure enantiomers.

It is understood that a compound as described herein may be substituted with any number of substituents or functional moieties. In general, the term "substituted" whether preceded by the term "optionally" and the substituents contained in the formulae herein, refers to the replacement of a hydrogen radical in a given structure with a radical of a particular substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a particular group, the substituents may be the same or different at each position. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. For the purposes of the present invention, a heteroatom such as nitrogen may have a hydrogen substituent and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatom. Further, the present invention is not intended to be limited in any way by the permissible substituents of organic compounds. Combinations of substituents and variables contemplated by the present invention are preferably those that result in the formation of stable compounds useful in the treatment of, for example, proliferative diseases. As used herein, the term "stable" preferably means that the compound has sufficient stability to allow manufacture, and that it maintains the integrity of the compound for a sufficient period of detection, and preferably for a sufficient period of time for the purposes detailed herein.

As used herein, the term "cancer" and, equivalently, "tumor" refers to a condition in which abnormally replicating cells of host origin are present in a detectable amount in a subject. The cancer may be a malignant or non-malignant cancer. Cancers or tumors include, but are not limited to: biliary tract cancer; brain cancer; breast cancer; cervical cancer; choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer; gastric (stomach) cancer; intraepithelial tumors; leukemia; lymphoma; liver cancer; lung cancer (e.g., small cell and non-small cell); melanoma; neuroblastoma; oral cancer; ovarian cancer; pancreatic cancer; prostate cancer; rectal cancer; renal (renal) carcinoma; a sarcoma; skin cancer; testicular cancer; thyroid cancer; and other carcinomas and sarcomas. The cancer may be primary or metastatic. Diseases other than cancer may be associated with mutations in Ras signaling pathway components, and the compounds disclosed herein may be used to treat these non-cancer diseases. Such non-cancer diseases may include: neurofibromatosis; leopard syndrome; noonan syndrome; legius syndrome (Legius syndrome); costello syndrome (Costello syndrome); cardio-facio-cutaneous syndrome (Cardio-facio-cutaneous syndrome); hereditary type 1 gingival fibromatosis; autoimmune lymphoproliferative syndrome; and capillary malformations-arterial fluid malformations.

As used herein, "effective amount" refers to any amount necessary or sufficient to achieve or facilitate the desired result. In some cases, the effective amount is a therapeutically effective amount. A therapeutically effective amount is any amount necessary or sufficient to promote or achieve a desired biological response in a subject. The effective amount for any particular application may vary depending on factors such as the disease or condition being treated, the particular agent being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine an effective amount of a particular agent without undue experimentation.

As used herein, the term "subject" refers to a vertebrate. In one embodiment, the subject is a mammal or a mammalian species. In one embodiment, the subject is a human. In other embodiments, the subject is a non-human vertebrate, including but not limited to, a non-human primate, a laboratory animal, a farm animal, a racehorse, a domesticated animal, and a non-domesticated animal.

Compound (I)

Novel compounds are described which are Kv1.3 potassium channel blockers. Applicants have surprisingly found that the compounds disclosed herein exhibit potent kv1.3 potassium channel inhibitory properties. Furthermore, applicants have surprisingly found that the compounds disclosed herein selectively block the kv1.3 potassium channel and do not block the hERG channel, and thus have desirable cardiovascular safety profiles.

In one aspect, compounds of formula I, or pharmaceutically acceptable salts thereof,

；

wherein

Z is OR_a、NR_aR_bOr NR_b(C=O)R_a；

X₁Is H, halogen, CN, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, or halocycloalkyl;

X₂is H, halogen, CN, alkyl, haloalkyl, cycloalkyl or halocycloalkyl;

X₃is H, halogen, fluoroalkyl or alkyl;

or X₁And X₂Together with the carbon atom to which they are attached form an optionally substituted 6-membered aryl group;

or X₂And X₃Together with the carbon atom to which they are attached form an optionally substituted 6-membered aryl group;

R₃is H, halogen or alkyl;

or X₁And R₃Together with the carbon atom to which they are attached formAn optionally substituted 6-membered aryl group;

R₁and R₂Each independently is H, alkyl, (CR)₆R₇)_n4OR_a、(CR₆R₇)_n4NR_aR_b、(CR₆R₇)_n4NR_a(C=O)R_b、(CR₆R₇)_n4NR_aSO₂R_bOr (CR)₆R₇)_n4CONR_aR_b(ii) a Or R₁、R₂Together with the carbon atom to which they are attached form a 3-5 membered carbocyclic ring;

R₄is H, alkyl, haloalkyl, optionally substituted cycloalkyl, (CR)₆R₇)_n4OR_c、(CR₆R₇)_n4(C=O)R_c、(C=O)(CR₆R₇)_n4R_c、(CR₆R₇)_n4COOR_c、(CR₆R₇)_n4NR_c(C=O)R_d、(CR₆R₇)_n4(C=O)NR_cR_d、(C=O)(CR₆R₇)_n4NR_cR_d、(CR₆R₇)_n4(C=O)(C=O)NR_cR_d、(C=O)(CR₆R₇)_n4OR_c、(CR₆R₇)_n4SO₂R_c、(CR₆R₇)_n4SO₂NR_cR_dOptionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted-alkyl-aryl, optionally substituted-alkyl-heteroaryl, optionally substituted-alkyl-heterocycle, optionally substituted-alkyl-cycloalkyl or optionally substituted-cycloalkyl-alkyl;

R₅Independently for each occurrence of (a) is H, alkyl, cycloalkyl or oxo;

or two R₅The groups together with the carbon atoms to which they are attached form a 3-7 membered optionally substituted saturated carbocyclic ring;

or two R₅The groups are attached to different carbon atoms on the carbocyclic ring and together form a bond or an alkyl chain containing 1-3 carbons;

R₆and R₇Each occurrence of (a) is independently H, alkyl, or cycloalkyl;

R_aand R_bEach occurrence of (a) is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl; or R_aAnd R_bTogether with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring containing the nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S;

R_cand R_dEach occurrence of (A) is independently H, alkyl, substituted with 1-4 independently of each other halogen, OR₈Or N (R)₈)₂Substituted alkyl, alkenyl, optionally substituted cycloalkyl, optionally substituted bicycloalkyl, optionally substituted spiroalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted-alkyl-aryl, optionally substituted-alkyl-heteroaryl, optionally substituted-alkyl-heterocycle, optionally substituted-alkyl-cycloalkyl or optionally substituted-cycloalkyl-alkyl; or R _cAnd R_dTogether with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring comprising the nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S;

R₈independently for each occurrence is H, alkyl or optionally substituted heterocycle; or two R₈The groups together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring comprising the nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S;

R₉is H, alkyl, halogen or (CR)₆R₇)_n4OR_a；

The alkyl, cycloalkyl, spiroalkyl, bicycloalkyl, heterocycle, aryl and heteroaryl groups are optionally substituted, where valency permits, with 1 to 4 substituents each independently selected from alkyl, cycloalkyl, halocycloalkyl, haloalkyl, halogen, CN, - (CH)₂)_0-2OR₈、N(R₈)₂、(C=O)C_1-4Alkyl, (C = O) N (R)₈)₂And oxo;

n when allowed by valence₁Each occurrence of (a) is independently an integer from 0 to 3;

n₂and n₃Each occurrence of (a) is independently an integer from 0 to 2; and

n₄each occurrence of (a) is independently an integer from 0 to 3.

In some embodiments, n is₂And n₃Each occurrence of (a) is independently an integer from 0 to 2. In some embodiments, n is₂And n₃Each is 0. In other embodiments, n ₂And n₃Each is 1. In yet other embodiments, n₂And n₃Each is 2. In some embodiments, n is₂And n₃Respectively 0 and 1. In some embodiments, n is₂And n₃Respectively 0 and 2. In some embodiments, n is₂And n₃Respectively 1 and 2.

In some embodiments, the structural motif

Has the advantages of

、

、

Or

Wherein the various substituents are as defined herein. In some embodiments, the structural motif

Has the advantages of

、

、

Or

Wherein the various substituents are as defined herein. In some embodiments, the structural motif

Has the advantages of

Wherein the various substituents are as defined herein.

In any of the embodiments described herein, R_aAnd R_bEach occurrence of (a) may be independently H, alkyl, cycloalkyl, saturated heterocycle, aryl or heteroaryl. In some embodiments, R_aAnd R_bAt least one of (a) is independently H, alkyl or cycloalkyl. In other embodiments, R_aAnd R_bAt least one of (a) is independently a saturated heterocycle, aryl or heteroaryl. In other embodiments, R_aAnd R_bTogether with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring containing the nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S.

In some embodiments, R₁And R₂Each is H or alkyl. In some embodiments, R₁And R₂Are all H. In some embodiments, R₁And R₂Is an alkyl group, such as Me, Et, propyl, isopropyl, n-butyl, isobutyl, or sec-butyl. In some embodiments, R₁And R₂Are H and alkyl, respectively.

In some embodiments, R₁And R₂At leastOne occurrence is (CR)₆R₇)_n4OR_aOr (CR)₆R₇)_n4NR_aR_b. In some embodiments, R₁And R₂At least one occurrence of (CR)₆R₇)_0-2NR_aR_b。NR_aR_bNon-limiting examples of (a) include: NH (NH)₂、NHMe、NMe₂、NHEt、NMeEt、NEt₂、NHPr、NMePr、NEtPr、NH(iso-Pr) and N: (iso-Pr)₂. In some embodiments, R₁And R₂At least one occurrence of (CR)₆R₇)_0-2OR_a。OR_aNon-limiting examples of (a) include: OH, OMe, OEt, OPr, O-iso-Pr、OBu、O-tertBu and O-sec-Bu. In some embodiments, R₁And R₂At least one occurrence of (A) is OR_aOr NR_aR_b。

In some embodiments, R₁And R₂At least one occurrence of (CR)₆R₇)_0-2NR_a(C=O)R_b、(CR₆R₇)_n4NR_aSO₂R_bOr (CR)₆R₇)_0-2CONR_aR_b。NR_a(C=O)R_bNon-limiting examples of (a) include: NH (C = O) Me, NMe (C = O) Me, NH (C = O) Et, NMe (C = O) Et, NEt (C = O) Et, NH (C = O) Pr, NMe (C = O) Pr, NEt (C = O) Pr, NH (C = O) ((C = O))iso-Pr)、NMe(C=O)(iso-Pr) and NEt (C = O) ((C = O)iso-Pr)。CONR_aR_bNon-limiting examples of (a) include: (C = O) NH₂、(C=O)NHMe、(C=O)NMe₂、(C=O)NHEt、(C=O)NMeEt、(C=O)NEt₂、(C=O)NHPr、(C=O)NMePr、(C=O)NEtPr、(C=O)NH(iso-Pr) and (C = O) N (C = O)iso-Pr)₂。

In other embodiments, R₁、R₂Together with the carbon atoms to which they are attached form a 3-5 membered carbocyclic ring. In some particular embodiments, R ₁、R₂Together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, or cyclopentyl group.

In some embodiments, R₁And R₂Each independently of the other is H, Me, OH, CH₂OH、NH₂、NHMe、NMe₂、CH₂NH₂、CONH₂、CONHMe₂、CONMe₂、NH(C=O)Me、NMe(C=O)Me、

。

In some embodiments, R₄Is H, alkyl, haloalkyl or cycloalkyl. In some particular embodiments, R₄Is H, Me, CF₃Or a fluoroethyl group.

In other embodiments, R₄Is (CR)₆R₇)_n4OR_c、(CR₆R₇)_n4COR_c、(C=O)(CR₆R₇)_n4R_c、(CR₆R₇)_n4COOR_c、(CR₆R₇)_n4NR_c(C=O)R_d、(CR₆R₇)_n4(C=O)NR_cR_d、(C=O)(CR₆R₇)_n4NR_cR_d、(CR₆R₇)_n4(C=O)(C=O)NR_cR_d、(C=O)(CR₆R₇)_n4OR_c、(CR₆R₇)_n4SO₂R_cOr (CR)₆R₇)_n4SO₂NR_cR_d. In some particular embodiments, n₄Is 0. In other particular embodiments, n₄Is 1 or 2. In some particular embodiments, R₄Is (CR)₆R₇)₂OR_c、(C=O)R_c、(C=O)(CR₆R₇)_1-2R_c、COOR_c、(CR₆R₇)_1-2NR_c(C=O)R_d、(C=O)NR_cR_d、(CR₆R₇)_n4(C=O)(C=O)NR_cR_d、(C=O)(CR₆R₇)_1-2OR_c、SO₂R_cOr SO₂NR_cR_d. In some particular embodiments, CR₆R₇Is CH₂、CHMe、CMe₂CHEt or CEt₂. In some particular embodiments, R₄Is (CH)₂)₂OH、(CH₂)₂OMe、(C=O)H、(C=O)Me、(C=O)CH₂OH、(C=O)CH₂OMe、(C=O)CH(OH)CH₂OH、(C=O)CH(OMe)CH₂OH、(C=O)CH(OH)CH₂OMe, (C = O) Et, (C = O) Ph, (C = O) isopropyl, (C = O) NH₂、(C=O)NHMe、(C=O)NMe₂、(C=O)CH₂NH₂、(C=O)CH₂NHMe、(C=O)(C=O)NMe₂、(C=O)OMe、SO₂Me、SO₂Et、SO₂CH₂OH、SO₂CH₂OMe、SO₂NH₂、SO₂NHMe or SO₂NMe₂. In other embodiments, R₄Is (C = O) CH (OH) CH₂OH、(C=O)CH(OMe)CH₂OH or (C = O) CH (OH) CH₂OMe。

In other embodiments, R₄Is (C = O) R_c、(C=O)(CR₆R₇)_1-2R_c、(C=O)(CR₆R₇)_1-2OR_cOr SO₂R_c(ii) a And wherein R_cSelected from H, alkyl, by being each independently selected from halogen, OR₈And N (R)₈)₂Alkyl substituted with 1 to 4 substituents of (1-4), alkenyl, optionally substituted cycloalkyl, optionally substituted bicycloalkyl, optionally substituted spiroalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted-alkyl-aryl, optionally substituted-alkyl-heteroaryl, optionally substituted-alkyl-heterocycle, optionally substituted-alkyl-cycloalkyl, and optionally substituted-cycloalkyl-alkyl.

In some embodiments, R_cOr R_dIs H, Me, Et,

Or

。

In some embodiments, R_cIs a heterocycle selected from:

(ii) a Wherein the heterocycle is optionally substituted, where valence permits, with one or more cyano, cycloalkyl, fluoroalkyl, fluorocycloalkyl, halogen, OH, NH₂Oxo or (C = O) C_1-4Alkyl substitution.

In some embodiments, R, where valence permits_cIs cycloalkyl, spiroalkyl or bicycloalkyl, each optionally substituted with 1-4 substituents, each independently selected from alkyl, halogen, CN, - (CH)₂)_0-2OR₈、N(R₈)₂、(C=O)N(R₈)₂And oxo. In other embodiments, the valency allowsIn the case of (1), R_cAre each optionally substituted by 1 to 4 substituents

Each of said substituents being independently selected from alkyl, halogen, CN, - (CH)₂)_0-2OR₈、N(R₈)₂、(C=O)N(R₈)₂And oxo.

In yet other embodiments, R₄Is optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted-alkyl-aryl, optionally substituted-alkyl-heteroaryl, optionally substituted-alkyl-heterocycle, optionally substituted-alkyl-cycloalkyl or optionally substituted-cycloalkyl-alkyl. In some particular embodiments, R ₄Is a heterocycle selected from:

(ii) a Wherein the heterocycle is optionally substituted, as valence permits, with one or more cyano, cycloalkyl, fluoroalkyl, fluorocycloalkyl, halogen, OH, NH₂Oxo or (C = O) C_1-4And (3) alkyl substitution.

In yet other embodiments, R, where valence permits, is₄Is optionally substituted by 1 to 4 substituentsCycloalkyl, each of said substituents being independently selected from alkyl, halogen, CN, - (CH)₂)_0-2OR₈、N(R₈)₂、(C=O)N(R₈)₂And oxo. In other embodiments, R, where valence permits, is₄Are each optionally substituted by 1 to 4 substituents

Each of said substituents being independently selected from alkyl, halogen, CN, - (CH)₂)_0-2OR₈、N(R₈)₂、(C=O)N(R₈)₂And oxo.

In some embodiments, R₈Is H or alkyl. In other embodiments, R₈Is an optionally substituted heterocycle. In yet other embodiments, two R are₈The groups, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclic ring comprising the nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S.

In some particular embodiments, R₄The method comprises the following steps:

or a tautomer thereof.

In some embodiments, R₅Is H, alkyl or cycloalkyl. In some particular embodiments, R ₅Is H. In other particular embodiments, R₅Is Me, Et, Pr,iso-Pr、Bu、iso-Bu、sec-Bu ortert-Bu. In other particular embodiments, R₅Is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In other particular embodiments, R₅Is oxo.

In other embodiments, two R are₅The groups, together with the carbon atoms to which they are attached, form a 3-7 membered optionally substituted saturated carbocyclic ring. In yet other embodiments, two R are₅The groups are attached to different carbon atoms on the carbocyclic ring and together form a bond or an alkyl chain containing 1-3 carbons.

In some embodiments, R₆And R₇Each occurrence of (a) is independently H or alkyl. In some particular embodiments, CR₆R₇Is CH₂、CHMe、CMe₂CHEt or CEt₂. In some particular embodiments, CR₆R₇Is CH₂。

In some embodiments, R₉Is H, alkyl or halogen. In other embodiments, R₉Is (CR)₆R₇)_n4OR_b. In some particular embodiments, R₉Is H, F or OH.

In any of the embodiments described herein, Z may be OR_a、NR_aR_bOr NR_b(C=O)R_a. In some embodiments, Z is OH, OMe, NH₂NHMe or NMe₂. In some embodiments, Z is OH.

In any of the embodiments described herein, X₁May be H, halogen, fluoroalkyl or alkyl. In some embodiments, X ₁Is cycloalkyl or cycloalkenyl. In some embodiments, X₁Is H, F, Cl, Br, Me, CF₃Or CF₂And (4) Cl. In some embodimentsIn, X₁Is H, F or Cl. In some embodiments, X₁Is Me or Cl.

In any of the embodiments described herein, X₂May be H, halogen, fluoroalkyl or alkyl. In some embodiments, X₂Is H, F, Cl, Br, Me, CF₃Or CF₂And (4) Cl. In some embodiments, X₂Is Cl or Br. In some embodiments, X₂Is Cl.

In any of the embodiments described herein, X₃Is H, F, Cl, Br, fluoroalkyl or alkyl. In some embodiments, X₃Is H, F, Cl or CF₃。

In some embodiments, a moiety

Having each of the radicals represented by R₃Substituted by

Or

The structure of (1).

In some embodiments, the compound of formula I has the structure of formula II,

；

wherein n is₆Is an integer of 0 to 2; r_3’Each occurrence of (a) is independently H, halogen, or alkyl; other substituents are as defined herein. In some embodiments, R_3’Is H or alkyl. Non-limiting examples of alkyl groups include: me, Et, propyl, isopropyl, n-butyl, isobutyl or sec-butyl. In other embodiments, R_3’Is halogen. In that In some embodiments, n₆Is 0. In some embodiments, n is₆Is 1. In some embodiments, n is₆Is 2.

In any of the embodiments described herein, R₃Is H, halogen or alkyl. In some embodiments, R₃Is H. In other embodiments, R₃Is an alkyl group such as Me, Et, propyl, isopropyl, n-butyl, isobutyl or sec-butyl. In yet other embodiments, R₃Is F, Cl or Br.

In any of the embodiments described herein, R₈Is H, alkyl or an optionally substituted heterocycle. In some embodiments, R₈Is H, Me, Et, Pr, Bu or a heterocycle selected from:

(ii) a Wherein the heterocycle is optionally substituted, where valence permits, with one or more cyano, cycloalkyl, fluoroalkyl, fluorocycloalkyl, halogen, OH, NH₂Oxo or (C = O) C_1-4Alkyl substitution.

In other embodiments, two R are₈The groups, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclic ring comprising the nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S.

In some embodiments, n is₁Is 0, 1, 2 or 3. In some particular embodiments, n₁Is 0 or 1. In some embodiments, n is ₄Is 0, 1 or 2. In some embodiments, n is₄Is 0 or 1. In some particular embodiments, n₄Is 0.

In any of the embodiments described herein, R_cOr R_dIs independently H, alkyl, is independently selected from halogen, OR₈And N (R)₈)₂Alkyl, alkenyl, optionally substituted cycloalkyl, optionally substituted bicycloalkyl, optionally substituted spiroalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted-alkyl-aryl, optionally substituted-alkyl-heteroaryl, optionally substituted-alkyl-heterocycle, optionally substituted-alkyl-cycloalkyl or optionally substituted-cycloalkyl-alkyl in the presence of 1 to 4 substituents of (a).

In some embodiments, R_cAnd R_dTogether with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring containing the nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S.

In some particular embodiments, R_cOr R_dIs independently H, Me, Et,

。

in some particular embodiments, R_cOr R_dIs independently a heterocycle selected from:

(ii) a Wherein the heterocycle is optionally substituted, where valence permits, with one or more cyano, cycloalkyl, fluoroalkyl, fluorocycloalkyl, halogen, OH, NH ₂Oxo or (C = O) C_1-4Alkyl substitution.

In some particular embodiments, R, where valence permits_cOr R_dIs cycloalkyl, spiroalkyl or bicycloalkyl, each optionally substituted with 1-4 substituents, each independently selected from alkyl, halogen, CN, - (CH)₂)_0-2OR₈、N(R₈)₂、(C=O)N(R₈)₂And oxo.

In some particular embodiments, R, where valence permits_cOr R_dIndependently of each other being optionally substituted by 1 to 4 substituents

Each of said substituents being independently selected from alkyl, halogen, CN, - (CH)₂)_0-2OR₈、N(R₈)₂、(C=O)N(R₈)₂And oxo.

In some embodiments, the compound of formula I is selected from compounds 1-338 shown in table 1 below.

Abbreviations

。

Preparation method

The following is a general synthetic scheme for making the compounds of the present invention. These schemes are illustrative and are not meant to limit the possible techniques available to those skilled in the art for preparing the compounds disclosed herein. Different methods will be apparent to those skilled in the art. In addition, the various steps in the synthesis may be performed in alternating order or sequence to obtain the desired compound. The following reactions are illustrative of, and not limiting to, the preparation of some of the starting materials and compounds disclosed herein.

Schemes 1-9 below describe synthetic routes that can be used to synthesize compounds of the invention, e.g., compounds having the structure of formula I or precursors thereof. Various modifications to these methods can be envisaged by those skilled in the art to achieve results similar to those of the present invention given below. In the following embodiments, synthetic routes are described using I-4, I-6, I-4a, I-6a, I-7b, I-10a and I-13 as examples. Other compounds of formula I may be prepared by using methods analogous to those described in schemes 1-9 or using methods known in the art. The general synthetic routes described in schemes 1-9 and the examples described in the examples section below illustrate methods for preparing the compounds described herein.

As shown in scheme 1, compound I-4 can be prepared from compound I-1a or I-1 b.

Compounds I-1a, I-1b, I-2a, I-2b and I-2c may be prepared by any method known in the art. As shown in scheme 1, "Br/I" refers to Br or I substituents, and PG refers to protecting groups. Non-limiting examples of protecting groups include: me, allyl, Ac, Boc, other alkoxycarbonyl, dialkylaminocarbonyl or any other known in the art to be suitable for use as OH or NH₂The protecting group of (1) is further protecting group. Other substituents are as defined herein. As shown in scheme 1, step I, the intermediate ketone I-3 can be prepared by reacting a protected phenol I-1a with an appropriately protected acid chloride in the presence of a Lewis acid I-2a by Friedel-crafts reaction. Non-limiting examples of lewis acids include aluminum III chloride. Alternatively, aryl bromide or iodide I-1b is converted to the corresponding Grignard reagent, for example by treatment with isopropyl magnesium chloride (R is isopropyl), or to the corresponding aryl lithium reagent by treatment with butyl lithium (step ii). The resulting organometallic reagent reacts with Weinreb amide I-2b to form ketone I-3. The ketone I-3 can be reduced using a suitable reducing agent to give the alcohol I-4 (step v). Non-limiting examples of suitable reducing agents include NaBH₄. Also alternatively, aryl bromide or iodide I-1b is converted to the corresponding Grignard reagent, for example by treatment with isopropyl magnesium chloride (R is isopropyl), or to the corresponding aryl lithium reagent by treatment with butyl lithium, and the resulting organometallic reagent is reacted with aldehyde I-2c to give benzyl alcohol I-4 (step vi). Benzyl alcohol I-4 can be oxidized to ketone I-3 using an oxidizing agent such as dess-martin periodate. The protecting group in compound I-4 can then be selectively removed, and the resulting compound having free NH and/or phenolic OH groups can optionally be converted to a compound of formula I using methods known in the art.

As shown in scheme 2, compound I-6 can be prepared from compound I-1b, I-2d, or I-3.

Compounds I-1b and I-2d can be prepared by any method known in the art. Compound I-3 can be prepared by the method shown in scheme 1. As shown in scheme 2, "Br/I" refers to Br or I substituents, and PG refers to protecting groups. Non-limiting examples of protecting groups include: me, allyl, Ac, Boc, other alkoxycarbonyl, dialkylaminocarbonyl or others known in the art to be suitable for use as OH or NH₂The protecting group of (1) is further protecting group. Other substituents are as defined herein. Scheme 2 step I shows, having formula I (wherein R₁Compounds comprising an amino group) (e.g., Compound I-6) can be formed from ketone I-3 by heating ketone I-3 with an alkylsulfinimide such as t-butylsulfenimide (i.e., R is an alkyl group such as t-butyl) in the presence of a Lewis acid (e.g., titanium tetraethoxide)Sulfinylimide I-5. Reduction of sulfinylimine I-5 with a reducing agent such as sodium borohydride or diisobutylaluminum hydride (DIBAL) affords sulfinylimine I-6 (step ii). The single enantiomer of compound I-6 can be prepared by methods known in the art. Alternatively, as shown in step iii, compound I-6 can be synthesized by forming a Grignard reagent or organolithium reagent from I-1b and reacting the formed Grignard reagent or organolithium reagent with sulfinimide I-2d (prepared from I-2c in scheme 1 using methods known in the art) to directly give I-6. The protecting group in compound I-6 can then be selectively removed, and the resulting compound having free NH and/or phenolic OH groups can optionally be converted to a compound of formula I using methods known in the art.

As shown in scheme 3, compounds I-3a, I-4a and I-6a can be prepared from compounds I-1d and I-2b, I-1d and I-2c, and I-1d and I-2d, respectively.

Compounds I-1d, I-2b, I-2c and I-2d can be prepared by any method known in the art. As shown in scheme 3, PG refers to a protecting group. Non-limiting examples of protecting groups include: me, allyl, Ac, Boc, other alkoxycarbonyl, dialkylaminocarbonyl or any other known in the art to be suitable for use as OH or NH₂The protecting group of (1) is further protecting group. Other substituents are as defined herein. As shown in scheme 3, steps I, ii or iii, a suitably protected phenol such as diethyl carbamate I-1d can be activated by lithiation of the carbamate ortho position and reacted with a Weinreb amide I-2b (step I), an aldehyde I-2c (step ii) or a sulfinimide I-2d (step iii), as shown in scheme 3. The protecting groups in compounds I-4a and I-6a may then be selectively removed, and the resulting compounds having free NH and/or phenolic OH groups may optionally be converted to compounds of formula I using methods known in the art. The ketone I-3a can be treated with a suitable reducing agent (e.g., NaBH)₄) Reduction to give the corresponding alcohol (not shown). The protecting group of the resulting alcohol may then be selectively removed and the resulting alcohol may be reacted The resulting compounds having free NH and/or phenolic OH groups are optionally converted to compounds of formula I by methods known in the art.

As shown in scheme 4, compounds I-4, I-3 '', and I-7 can be prepared from compound I-3.

Compound I-3 can be prepared by the method shown in scheme 1. As shown in scheme 4, PG refers to a protecting group. Non-limiting examples of protecting groups include: me, allyl, Ac, Boc, other alkoxycarbonyl, dialkylaminocarbonyl or any other known in the art to be suitable for use as OH or NH₂The protecting group of (1) is further protecting group. Other substituents are as defined herein. As shown in scheme 4 for R₁ = R₂Compound of formula I (e.g. compound I-7) with H ketone I-3 is reduced to alcohol I-4 with a reducing agent (e.g. sodium borohydride) (step I). Alcohol I-4 is then reduced with a silane such as triethylsilane in the presence of a Lewis acid such as boron trifluoride etherate or an acid such as trifluoroacetic acid to give compound I-7 (step ii). When the nitrogen protecting group is Boc, the nitrogen protecting group is removed under these conditions to give the benzyl cyclic amine I-7. For R₁Is an alkyl compound, ketone I-3 is treated with a suitable alkyl-Grignard reagent (e.g., R)₁MeBr) to give alcohol I-3' (step iii). As shown in scheme 4, step iv, the alcohol I-3 ' can be reduced with triethylsilane to remove the OH group using a method similar to that used in step ii, to give compound I-3 ' ' (when the nitrogen protecting group is Boc, the nitrogen protecting group is removed under these conditions). The protecting groups in compounds I-3 '' and I-7 can then be selectively removed, and the resulting compounds having free phenolic OH groups can optionally be converted to compounds of formula I using methods known in the art.

As shown in scheme 5, compound I-7 can be prepared from compounds I-8 and I-9.

Compounds I-8, I-9a and I-9 can be prepared by any method known in the art. As shown in scheme 5, PG refers to a protecting group. Non-limiting examples of protecting groups include: me, allyl, Ac, Boc, other alkoxycarbonyl, dialkylaminocarbonyl or any other known in the art to be suitable for use as OH or NH₂The additional protecting group of (1). The other substituents are as defined herein. As shown in scheme 5, preparation of a compound wherein R₁ = R₂= H and n₂ = n₃An alternative route to compounds of formula I of = 1 is to react benzyl bromide I-8 with pyridine boronic acid or boronic ester I-9(R is H or alkyl) using a palladium catalyst such as tetrakis (triphenylphosphine) palladium to give benzyl pyridine I-10 (step I). Reduction of pyridine I-10 by a reducing agent (e.g., hydrogen on platinum oxide in the presence of an acid such as HCl) affords benzylpiperidine I-7 b. Alternatively, vinyl borate I-9a may be used in analogy to steps (steps iii and iv) to give compound I-7 b. In steps I and iii, a base such as Na may be used₂CO₃. The protecting group in compound I-7b can then be selectively removed, and the resulting compound having free NH and phenolic OH groups can optionally be converted to a compound of formula I using methods known in the art.

As shown in scheme 6, compound I-7 can be prepared from compounds I-1b and I-11.

Compounds I-11 and I-1b can be prepared by any method known in the art. As shown in scheme 6, PG refers to a protecting group. Non-limiting examples of protecting groups include: me, allyl, Ac, Boc, other alkoxycarbonyl, dialkylaminocarbonyl or others known in the art to be suitable for use as OH or NH₂The additional protecting group of (1). The other substituents are as defined herein. As shown in scheme 6, preparation of compounds wherein R₁ = R₂Other routes for compounds of formula I with = H are hydroboration of exocyclic alkenylcyclic amines I-8 using palladium catalysts (e.g. Pd (dppf) Cl₂) Reacting the obtained borate with bromine or iodinePhenol I-1b coupling. The protecting group in compound I-7 can then be selectively removed, and the resulting compound having free NH and/or phenolic OH groups can optionally be converted to a compound of formula I using methods known in the art.

As shown in scheme 7, compound I-7 can also be prepared from compounds I-1b and I-12.

Compounds I-12 and I-1b may be prepared by any method known in the art. As shown in scheme 7, PG refers to a protecting group. Non-limiting examples of protecting groups include: me, allyl, Ac, Boc, other alkoxycarbonyl, dialkylaminocarbonyl or any other known in the art to be suitable for use as OH or NH ₂The additional protecting group of (1). The other substituents are as defined herein. As shown in scheme 7, preparation of compounds wherein R₁ = R₂Other routes to compounds of formula I of = H are to use a combination of tris (trimethylsilyl) silane, iridium and nickel catalysts under blue LED lamp illumination (e.g. Ir [ dF (CF) respectively₃)ppy]₂(dtbbpy)PF₆And NiCl₂) Photooxidation of bromophenol I-1b and bromomethylcycloamine I-12. The protecting group in compound I-7 can then be selectively removed, and the resulting compound having free NH and/or phenolic OH groups can optionally be converted to a compound of formula I using methods known in the art.

As shown in scheme 8, compound I-13 can be prepared from compounds I-8 and I-2 d.

Compounds I-8 and I-2d can be prepared by methods known in the art. As shown in scheme 8, PG refers to a protecting group. Non-limiting examples of protecting groups include: me, allyl, Ac, Boc, other alkoxycarbonyl, dialkylaminocarbonyl or any other known in the art to be suitable for use as OH or NH₂Additional protection of the protecting group of (2)And (4) protecting the base. Other substituents are as defined herein. As shown in scheme 8, with substituent R₉The compound of formula I can be obtained by reacting a cyclic amine I-2d containing an Electron Withdrawing Group (EWG) such as an ester or nitrile with benzyl bromide I-8 in the presence of a base such as sodium hexamethyldisilazide (sodium hexamethyldisilazide) to give compound I-13. Any suitable base may be used for this reaction. The ester or nitrile group (or other electron withdrawing group) in compound I-13 can be converted to R as defined herein by methods known in the art ₉The range of groups. The resulting compound having the desired R can then be selectively removed₉Protecting groups in the compounds of the groups, and the resulting compounds having free NH and/or phenolic OH groups may optionally be converted to compounds of formula I using methods known in the art.

With other R₁And R₂Substituted compounds of formula I can be synthesized from ketones I-3 by, for example, reductive amination, wittig reaction followed by cyclopropanation or hydroboration, or from alcohols I-4 by conversion to the corresponding bromide and displacement of the bromide with a nucleophile.

As shown in scheme 9, wherein R₁Is NH₂、n₂=1 and n₃Compounds of formula (I) of =1 (e.g. compounds I-16 and I-17) can be prepared from compounds I-1e and I-14.

Compounds I-14 and I-1e may be prepared by any method known in the art. As shown in scheme 9, the three-component reaction of phenol I-1e, pyridine aldehyde I-14 and acetamide is carried out by optionally heating all three components with aluminum trichloride in the absence of a solvent to provide acetamide I-15. Hydrogenation on platinum oxide reduced pyridine to piperidine I-16 and acid hydrolysis gave amine I-17.

The reactions described in schemes 1-9 can be carried out in a suitable solvent. Suitable solvents include, but are not limited to, acetonitrile, methanol, ethanol, dichloromethane, DMF, THF, MTBE, or toluene. The reactions described in schemes 1-9 can be carried out under inert conditions The reaction may be carried out under a neutral atmosphere, for example under nitrogen or argon, or the reaction may be carried out in a sealed tube. The reaction mixture may be heated in a microwave or to an elevated temperature. Suitable elevated temperatures include, but are not limited to, 40, 50, 60, 80, 90, 100, 110, 120 ℃ or higher, or the reflux/boiling temperature of the solvent used. Alternatively, the reaction mixture may be cooled in a cold bath at a temperature below room temperature, e.g., 0, -10, -20, -30, -40, -50, -78, or-90 ℃. The reaction may be carried out by removing the solvent or partitioning the organic solvent phase with one or more aqueous phases, each optionally containing NaCl, NaHCO₃Or NH₄And (4) Cl. The solvent in the organic phase can be removed by evaporation under reduced pressure, and the resulting residue can be purified using a silica gel column or HPLC.

Pharmaceutical composition

The present invention also provides a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

In yet another aspect, the present invention provides a pharmaceutical composition comprising at least one compound selected from compounds of formula I as described herein and a pharmaceutically acceptable carrier or diluent.

In certain embodiments, the composition is in the form of a hydrate, solvate, or pharmaceutically acceptable salt. The compositions may be administered to a subject by any suitable route of administration, including, but not limited to, oral and parenteral administration.

As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting a subject agent from one organ or portion of the body to another organ or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Examples of some materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; astragalus membranaceus gel powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as butanediol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; ringer's solution; ethanol; phosphate buffer; and other non-toxic compatible materials for use in pharmaceutical formulations. The term "carrier" denotes a natural or synthetic organic or inorganic ingredient with which the active ingredient is combined to facilitate application. The components of the pharmaceutical composition can also be blended with the compounds of the present invention and with each other so that there are no interactions that would significantly impair the desired pharmaceutical efficiency.

As noted above, certain embodiments of the agents of the present invention may be provided in the form of pharmaceutically acceptable salts. In this regard, the term "pharmaceutically acceptable salts" refers to the relatively non-toxic inorganic and organic acid addition salts of the compounds of the present invention. These salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting the purified compounds of the invention in free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate, dodecylsulfonate, and the like. (see, e.g., Berge et al, (1977) "Pharmaceutical Salts",J. Pharm. Sci.66:1-19.)

pharmaceutically acceptable salts of the subject compounds include the conventional non-toxic salts or the quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochlorides, hydrobromides, sulfates, sulfamates, phosphates, nitrates, and the like; and salts prepared from organic acids such as acetic acid, butyric acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothioic acid, and the like.

In other cases, the compounds of the invention may contain one or more acidic functional groups and are therefore capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these cases, the term "pharmaceutically acceptable salts" refers to the relatively non-toxic, inorganic and organic base addition salts of the compounds of the present invention. These salts can also be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (see, e.g., Berge et al, supra).

Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate, magnesium stearate and polyethylene oxide-polybutylene oxide copolymers, as well as coloring agents, mold release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

The formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally that amount of the compound which produces a therapeutic effect. Typically, this amount will range from about 1% to about 99% of the active ingredient in 100%, preferably from about 5% to about 70%, most preferably from about 10% to about 30%.

Methods of preparing these formulations or compositions include the step of bringing into association a compound of the invention with a carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compounds of the invention with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base such as gelatin and glycerin, or sucrose and acacia) and/or as mouthwashes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. The compounds of the invention may also be administered in the form of a bolus, electuary or paste.

In the solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.) of the present invention, the active ingredient is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate and sodium starch glycolate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol, glyceryl monostearate, and polyethylene oxide-polybutylene oxide copolymers; absorbents such as kaolin and bentonite clay; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; and a colorant. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar (milk sugars) and high molecular weight polyethylene glycols.

Tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxybutyl methylcellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

Tablets and other solid dosage forms of the pharmaceutical compositions of the invention, such as dragees, capsules, pills and granules, can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may also be formulated to provide slow or controlled release of the active ingredient therein, for example using hydroxybutyl methyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which may be dissolved in sterile water or some other sterile injectable medium immediately prior to use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferably, in a certain part of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymers and waxes. The active ingredient may also be in microencapsulated form, optionally together with one or more of the above excipients.

Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isobutyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, butylene glycol, 1, 3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Additionally, cyclodextrins, such as hydroxybutyl- β -cyclodextrin, can be used to solubilize compounds.

In addition to inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Dosage forms for topical or transdermal administration of the compounds of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

Ointments, pastes, creams and gels may contain, in addition to an active compound of the invention, excipients, for example, animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

In addition to the compounds of the invention, powders and sprays can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as propane and butane.

Transdermal patches have the additional advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms may be prepared by dissolving or dispersing the agent in a suitable medium. Absorption enhancers may also be used to increase the flux of the agents of the invention through the skin. The rate of such flux can be controlled by providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions, and the like are also within the scope of this invention.

Pharmaceutical compositions of the invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

In some cases, to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material which is poorly water soluble. The rate of absorption of the drug depends on its rate of dissolution, which in turn depends on crystal size and crystal form. Alternatively, delayed absorption of a parenterally administered drug form is achieved by dissolving or suspending the drug in an oil medium. One strategy for depot injection involves the use of polyethylene oxide-polypropylene oxide copolymers, where the medium is fluid at room temperature and cures at body temperature.

Injectable depot forms are prepared by forming microcapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

When the compounds of the present invention are administered as medicaments to humans and animals, they may be administered as such or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably 0.5% to 90%) of the active ingredient together with a pharmaceutically acceptable carrier.

The compounds and pharmaceutical compositions of the present invention may be used in combination therapy, i.e., the compounds and pharmaceutical compositions may be administered simultaneously, prior to, or after one or more other desired therapeutic or medical procedures. The particular combination of therapies (therapeutic agents or methods) used in a combination regimen will take into account the compatibility of the desired therapeutic agent and/or method and the desired therapeutic effect to be achieved. It is also understood that the therapy employed may achieve the desired effect on the same condition (e.g., the compound of the invention may be administered concurrently with another therapeutic agent). Non-limiting examples of other therapeutic agents include biological and small molecule anti-cancer agents, immunomodulators, immunosuppressants, anti-inflammatory agents, anti-arthritic agents, corticosteroids, antidiarrheal agents, anticoagulants, and antithrombotic agents.

The compounds of the present invention may be administered intravenously, intramuscularly, intraperitoneally, subcutaneously, topically, orally, or by other acceptable means. The compounds are useful for treating arthritic conditions in mammals (e.g., humans, domestic animals and domestic animals), racehorses, birds, lizards, and any other organism that can tolerate the compounds.

The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical composition of the invention. Optionally, associated with such a container may be a notice in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

Administration to a subject

In another aspect, the present invention provides a method of treating a condition in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound selected from a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the condition is selected from cancer, an immune disorder, a Central Nervous System (CNS) disorder, an inflammatory disorder, a gastrointestinal disorder, a metabolic disorder, a cardiovascular disorder, and a renal disorder.

In some embodiments, the cancer is selected from biliary cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, colon cancer, endometrial cancer, esophageal cancer, gastric (stomach) cancer, intraepithelial tumors, leukemia, lymphoma, liver cancer, lung cancer, melanoma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, renal (kidney) cancer, sarcoma, skin cancer, testicular cancer, and thyroid cancer.

In some embodiments, the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontitis, or an inflammatory neuropathy. In some embodiments, the gastrointestinal disorder is an inflammatory bowel disease such as crohn's disease or ulcerative colitis.

In some embodiments, the immune disorder is transplant rejection or an autoimmune disease (e.g., rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes). In some embodiments, the Central Nervous System (CNS) disorder is alzheimer's disease.

In some embodiments, the metabolic disorder is obesity or type II diabetes. In some embodiments, the cardiovascular disorder is ischemic stroke. In some embodiments, the kidney disease is chronic kidney disease, nephritis, or chronic renal failure.

In some embodiments, the mammalian species is a human.

In some embodiments, the condition is selected from the group consisting of cancer, transplant rejection, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes, alzheimer's disease, inflammatory skin conditions, inflammatory neuropathy, psoriasis, spondylitis, periodontitis, inflammatory bowel disease, obesity, type II diabetes, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and combinations thereof.

In yet another aspect, a method of blocking kv1.3 potassium channels in a mammalian species in need thereof is described comprising administering to the mammalian species a therapeutically effective amount of at least one compound of formula I, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds described herein are selective in blocking Kv1.3 potassium channels, with minimal or no off-target inhibitory activity on other potassium channels or on calcium or sodium channels. In some embodiments, the compounds described herein do not block the hERG channel and therefore have desirable cardiovascular safety properties.

Some aspects of the invention relate to administering an effective amount of a composition to a subject to achieve a particular result. Thus, small molecule compositions useful according to the methods of the invention may be formulated in any manner suitable for pharmaceutical use.

The formulations of the present invention are administered in the form of pharmaceutically acceptable solutions which may generally contain pharmaceutically acceptable concentrations of salts, buffers, preservatives, compatible carriers, adjuvants and optionally other therapeutic ingredients.

For use in therapy, an effective amount of the compound may be administered to a subject by any means that allows the compound to be taken up by the appropriate target cells. "administration" of the pharmaceutical compositions of the present invention may be accomplished by any method known to those skilled in the art. Specific routes of administration include, but are not limited to: oral, transdermal (e.g., via patch), parenteral injection (subcutaneous, intradermal, intramuscular, intravenous, intraperitoneal, intrathecal, etc.), or mucosal (intranasal, intratracheal, inhalation, intrarectal, intravaginal, etc.). The injection may be a bolus injection or a continuous infusion.

For example, the pharmaceutical compositions according to the invention are generally administered intravenously, intramuscularly or by other parenteral means. They may also be administered intranasally, by inhalation, topically, orally or as implants, even rectal or vaginal use is possible. Suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for injection or inhalation, microencapsulation, cochlear formation (encochleared), coating onto gold microparticles, inclusion in liposomes, nebulization, aerosols, pellets for implantation into the skin or dry sharp objects to scratch into the skin. The pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro) capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with extended release of the active compound, in which preparations excipients and additives and/or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are conventionally used as described above. The pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of current drug delivery methods, see Langer R (1990) Science 249:1527-33, which is incorporated herein by reference.

The concentration of the compound included in the compositions used in the methods of the invention can range from about 1 nM to about 100. mu.M. An effective dose is believed to be in the range of about 10 pmol/kg to about 100 micromol/kg.

The pharmaceutical compositions are preferably prepared and administered in dosage units. Liquid dosage units are vials or ampoules for injection or other parenteral administration. Solid dosage units are tablets, capsules, powders and suppositories. For the treatment of patients, different dosages may be required depending on the activity of the compound, the mode of administration, the purpose of administration (i.e. prophylactic or therapeutic), the nature and severity of the condition, the age and weight of the patient. Administration of a given dose can be carried out by a single administration in the form of an individual dosage unit or several smaller dosage units. Repeated and multiple administrations at specific intervals of days, weeks or months are also contemplated by the present invention.

The compositions may be administered as such (neat) or in the form of a pharmaceutically acceptable salt. When used in medicine, the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof. These salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluenesulfonic, tartaric, citric, methanesulfonic, formic, malonic, succinic, naphthalene-2-sulfonic, and benzenesulfonic acids. Likewise, these salts may be prepared as alkali metal or alkaline earth metal salts, for example sodium, potassium or calcium salts of carboxylic acid groups.

Suitable buffers include: acetic acid and salts (1-2% w/v); citric acid and salts (1-3% w/v); boric acid and salts (0.5-2.5% w/v); and phosphoric acid and salts (0.8-2% w/v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w/v); chlorobutanol (0.3-0.9% w/v); parabens (0.01-0.25% w/v) and thimerosal (0.004-0.02% w/v).

Compositions suitable for parenteral administration conveniently include sterile aqueous preparations which are isotonic with the blood of the recipient. Among the acceptable carriers and solvents are water, ringer's solution, phosphate buffered saline and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed mineral or non-mineral oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Suitable carrier formulations for subcutaneous, intramuscular, intraperitoneal, intravenous administration and the like may be usedRemington's Pharmaceutical SciencesMack Publishing Company, Easton, Pa.

The compounds useful in the present invention may be delivered as a mixture of two or more such compounds. The mixture may include one or more adjuvants in addition to the combination of compounds.

There are various routes of administration. The particular mode selected will, of course, depend on the particular compound selected, the age and general health of the subject, the particular condition being treated, and the dosage required for therapeutic efficacy. In general, the methods of the invention may be practiced using any medically acceptable mode of administration, i.e., any mode that produces an effective level of response without causing clinically unacceptable side effects. Preferred modes of administration are as described above.

The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the compound with the carrier which constitutes one or more accessory ingredients. Generally, the compositions are prepared by uniformly and intimately bringing the compound into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.

Other delivery systems may include time-release, delayed release, or sustained release delivery systems. Such a system may avoid repeated administration of the compound, increasing convenience to the subject and physician. Many types of delivery systems are available and known to those of ordinary skill in the art. They include polymer-based systems such as poly (lactide-co-glycolide), copolyoxalates, polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acid, and polyanhydrides. Microcapsules containing the aforementioned polymers of drugs are described, for example, in U.S. Pat. No. 5,075,109. The delivery system further comprises a non-polymeric system which is: lipids including sterols such as cholesterol, cholesterol esters and fatty acids or neutral fats such as monoglycerides, diglycerides and triglycerides; a hydrogel release system; a silicone rubber system; a peptide-based system; coating with wax; tableting using conventional binders and excipients; a partially fused implant; and so on. Specific examples include, but are not limited to: (a) an erosion system in which the agents of the invention are contained in an intramatrix form, such as those described in U.S. Pat. Nos. 4,452,775, 4,675,189, and 5,736,152, and (b) a diffusion system in which the active component permeates from the polymer at a controlled rate, such as those described in U.S. Pat. Nos. 3,854,480, 5,133,974, and 5,407,686. In addition, pump-based hardware delivery systems may be used, some of which are adapted for implantation.

Determination of the effectiveness of Kv1.3 Potassium channel blockers

In some embodiments, the compounds described herein are tested for activity on kv1.3 potassium channels. In some embodiments, the compounds described herein are tested for kv1.3 potassium channel electrophysiology. In some embodiments, the compounds described herein are tested for hERG electrophysiology.

Equivalents of the same

The following representative examples are intended to aid in the description of the invention, and are not intended, nor should they be construed, to limit the scope of the invention. Indeed, various modifications of the invention and many other embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the entirety herein, including the following examples and references to the scientific and patent literature cited herein. It should also be understood that the contents of these cited references are incorporated herein by reference to help explain the state of the art. The following examples contain important additional information, exemplification and guidance which can be adapted to the practice of the invention in its various embodiments and equivalents thereof.

Examples

Examples 1-76 describe various intermediates useful in the synthesis of representative compounds of formula I disclosed herein.

EXAMPLE 1 intermediate 1 (1- (4- (4, 5-dichloro-2-hydroxybenzoyl) piperidin-1-yl) ethanone)

A, step a:

to a stirred solution of 1-acetylpiperidine-4-carboxylic acid (2.00 g, 11.68 mmol) in DCE (20 mL) was added dropwise SOCl under nitrogen at 0 deg.C₂(10 mL). The reaction solution was warmed to room temperature. After stirring at room temperature for a further 1.5 h, the resulting solution was concentrated under reduced pressure to give crude 1-acetylpiperidine-4-carbonyl chloride, which was used in the next step without further purification.

Step b:

to a solution of 1-acetylpiperidine-4-carbonyl chloride (0.39 g, 2.03 mmol) in DCE (20 mL) was added 1, 2-dichloro-4-methoxybenzene (0.30 g, 1.69 mmol) at room temperature under a nitrogen atmosphere. After stirring for 5 minutes, anhydrous AlCl was added in portions at 0 ℃ under nitrogen atmosphere₃(0.49 g, 3.73 mmol). The reaction mixture was warmed to 50 ℃ and stirred under nitrogen for 2 hours. After cooling to 0 deg.C, the resulting mixture was quenched with ice water (30 mL) and extracted with DCM (3X 30 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with DCM/MeOH (10/1) to give the crude product as a dark yellow solid. The crude product was purified by preparative HPLC under the following conditions: column: sunfire Prep C18 OBD column, 10 μm, 19X 250 mm; mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 56% B to 64% B in 9 minutes; a detector: UV 254/210 nm; retention time: 6.98 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give 1- (4- (4, 5-dichloro-2-hydroxybenzoyl) piperidin-1-yl) ethanone as an off-white solid (85.6 mg, 16%): C₁₄H₁₅Cl₂NO₃ [M + H]⁺Calculated lcms (esi): 316, 318 (3: 2), found 316, 318 (3: 2);¹H NMR (300 MHz, DMSO-d ₆) δ 11.65 (s, 1H), 7.94 (s, 1H), 7.22 (s, 1H), 4.31 (d, J = 13.2 Hz, 1H), 3.85 (d, J = 13.2 Hz, 1H), 3.69-3.54 (m, 1H), 3.21-3.03 (m, 1H), 2.75-2.58 (m, 1H), 1.96 (s, 3H), 1.86-1.71 (m, 2H), 1.53-1.18 (m, 2H)。

EXAMPLE 2 intermediate 2 ((4, 5-dichloro-2-hydroxyphenyl) (piperidin-4-yl) methanone)

Step a:

1- [4- [ (4, 5-dichloro-2-hydroxyphenyl) carbonyl group]Piperidin-1-yl radical]Ethan-1-one (0.15 g, 0.48 mmol) in aqueous HCl (6)N15 mL) was stirred at 105 ℃ for 4 hours. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column 19X 250 mm, 10 μm; mobile phase A: having a NH concentration of 10 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 20% B to 60% B in 9 minutes; a detector: UV 254/210 nm; retention time: 8.5 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give (4, 5-dichloro-2-hydroxyphenyl) (piperidin-4-yl) methanone (23.5 mg, 18%) as a yellow solid as C ₁₂H₁₃Cl₂NO₂ [M + H]⁺Calculated lcms (esi): 274, 276 (3: 2), found 274, 276 (3: 2);¹H NMR (300 MHz, DMSO-d ₆) δ 7.85 (br, 1H), 7.57 (s, 1H), 6.67 (s, 1H), 3.96-3.76 (m, 1H)。3.12 (d, J = 12.0 Hz, 2H), 2.83-2.62 (m, 2H), 1.81 (d, J = 13.1 Hz, 2H), 1.57-1.34 (m, 2H)。

EXAMPLE 3 intermediate 3 (4- (amino (4, 5-dichloro-2-methoxyphenyl) methyl) piperidine-1-carboxylic acid tert-butyl ester trifluoroacetic acid)

Step a:

to a stirred solution of tert-butyl 4- (4, 5-dichloro-2-hydroxybenzoyl) piperidine-1-carboxylate (1.00 g, 2.68 mmol) in DMF (10 mL) at room temperature under nitrogen was added K₂CO₃(0.74 g, 5.36 mmol) and CH₃I (0.75 g, 5.36 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. The resulting mixture was diluted with water (60 mL) and extracted with EA (3X 50 mL) at room temperature. The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (4/1) to give tert-butyl 4- (4, 5-dichloro-2-methoxybenzoyl) piperidine-1-carboxylate (0.85 g, 83%) as a pale yellow solid as C₁₈H₂₃Cl₂NO₄ [M + H]⁺Calculated lcms (esi): 388, 390 (3: 2), found 388, 390 (3: 2);

step b:

to a stirred mixture of 4- [ (4, 5-dichloro-2-methoxyphenyl) carbonyl and water at 0 deg.C]To a solution of tert-butyl piperidine-1-carboxylate (1.70 g, 4.38 mmol) in THF (20 mL) was added NaBH portionwise ₄(0.25 g, 6.58 mmol). After stirring for a further 1.5 hours, the reaction mixture is taken up with saturated NH₄Aqueous Cl (50 mL) was quenched and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with DCM/MeOH (30/1) to give tert-butyl 4- ((4, 5-dichloro-2-methoxyphenyl) (hydroxy) methyl) cyclohexane-1-carboxylate (1.40 g, 82%) as an off-white solid₁₈H₂₅Cl₂NO₄ [M + H]⁺Calculated lcms (esi): 390, 392 (3: 2), found 390, 392 (3: 2);¹H NMR (300 MHz, DMSO-d ₆) δ 7.41 (s, 1H), 7.19 (s, 1H), 5..22 (d, J = 5.0 Hz, 1H), 4.61 (t, J = 5.2 Hz, 1H), 4.25 (d, J = 5.8 Hz, 1H), 3.99 (d, J = 5.8 Hz, 1H), 3.76 (s, 3H), 2.91-2.74 (m, 2H), 1.84-1.71 (m, 2H), 1.35 (s, 9H), 1.32-1.01 (m, 3H)。

step c:

to a stirred mixture of 4- [ (4, 5-dichloro-2-methoxyphenyl) (hydroxy) methyl group at 0 deg.C]Piperidine-1-carboxylic acid tert-butyl ester (2.50 g, 6.41 mmol) in DCM (18 mL) was added PBr dropwise₃(3.50 g, 12.81 mmol). After stirring for a further 1 h, the reaction solution is taken up with saturated NaHCO at 0 deg.C₃Aqueous solution (30 mL) was quenched and extracted with EA (3X 20 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give crude 4- (bromo (4, 5-dichloro-2-methoxyphenyl) methyl) piperidine, which was used in the next step without further purification: c ₁₃H₁₆BrCl₂NO [M + H]⁺Lcms (esi) calculated value of (a): 352, 354, 356 (2: 3: 1), found 352, 354, 356 (2: 3: 1).

Step d:

to a stirred solution of 4- [ bromo (4, 5-dichloro-2-methoxyphenyl) methyl at 0 deg.C]Piperidine (2.00 g, 5.66 mmol) and Et₃Boc was added dropwise to a solution of N (0.90 g, 8.50 mmol) in DCM (20 mL)₂A solution of O (1.90 g, 8.50 mmol) in DCM (5 mL). After stirring at 0 ℃ for an additional 1 hour, the resulting solution was concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with PE/EA (10/1) to give tert-butyl 4- (bromo (4, 5-dichloro-2-methoxyphenyl) methyl) piperidine-1-carboxylate (0.30 g, 12% in two steps in total) as a yellow oil, C₁₈H₂₄BrCl₂NO₃ [M + 1 - 56]⁺Calculated lcms (esi): 396, 398, 400 (2: 3: 1), found 396, 398, 400 (2: 3: 1);¹H NMR (300 MHz, CDCl₃) δ 7.50 (s, 1H), 6.95 (s, 1H), 5.15 (d, J = 9.4 Hz, 1H), 4.18 (d, J = 13.5 Hz, 1H), 4.03 (d, J = 13.8 Hz, 1H), 3.85 (s, 3H), 2.81-2.54 (m, 2H), 2.27-2.02 (m, 2H), 1.48 (s, 9H), 1.32-0.97 (m, 3H)。

step e:

to a stirred solution of tert-butyl 4- (bromo (4, 5-dichloro-2-methoxyphenyl) methyl) piperidine-1-carboxylate (0.26 g, 0.58 mmol) in DMF (5 mL) at room temperature was added NaN₃(0.11 g, 1.74 mmol). The reaction mixture was warmed to 100 ℃ and stirred for 16 hours. The reaction mixture was diluted with water (30 mL) and extracted with EA (3X 20 mL). The combined organic layers were washed with water (2X 15 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated to one-quarter volume under reduced pressure. The residue was used without further purification in the next step: c ₁₈H₂₄Cl₂N₄O₃ [M + H]⁺Lcms (esi) calculated value of (a): 415, 417 (3: 2), found 415, 417 (3: 2).

Step f:

to a stirred 4- [ azido (4, 5-dichloro-2-methoxyphenyl) methyl group at room temperature]Piperidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.48 mmol) and PPh₃(0.25 g, 0.96 mmol) in THF (2 mL) NH was added dropwise₃

H₂O (1 mL, 28% in H)₂In O). The reaction solution was stirred at room temperature for 16 hours. The resulting solution was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 30% aqueous ACN (plus 0.05% TFA) to give tert-butyl 4- (amino (4, 5-dichloro-2-methoxyphenyl) methyl) piperidine-1-carboxylate trifluoroacetic acid (0.10 g, 45% two steps in total) as a yellow oil, C₁₈H₂₆Cl₂N₂O₃ [M + H]⁺Calculated lcms (esi): 389, 391 (3: 2), found 389, 391 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.46 (s, 1H), 7.29 (s, 1H), 4.21-4.09 (m, 2H), 4.05-3.93 (m, 1H), 3.86 (s, 3H), 2.82-2.53 (m, 1H), 2.20-2.06 (m, 2H), 1.95-1.83 (m, 1H), 1.40 (s, 9H), 1.32-0.97 (m, 3H)。

EXAMPLE 4 intermediate 4 (1- (4- (amino (4, 5-dichloro-2-methoxyphenyl) methyl) piperidin-1-yl) ethanone)

Step a:

to a stirred mixture of 1- [4- (4, 5-dichloro-2-hydroxybenzoyl) piperidin-1-yl at room temperature under a nitrogen atmosphere]To a solution of ethan-1-one (1.00 g, 3.16 mmol) in DMF (10 mL) was added K₂CO₃(0.87 g, 6.33 mmol) and CH₃I (0.90 g, 6.33 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. The resulting mixture was diluted with water (60 mL) and extracted with EA (3X 50 mL) at room temperature. The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with PE/EA (4/1) to give 1- [4- (4, 5-dichloro-2-methoxybenzoyl) piperidin-1-yl group as a pale yellow solid]Ethan-1-one (1.00 g, 95%): C₁₅H₁₇Cl₂NO₃ [M + H]⁺Calculated lcms (esi): 330, 332 (3: 2), found 330, 332 (3: 2).

Step b:

to a stirred mixture of 1- [4- [ (4, 5-dichloro-2-methoxyphenyl) carbonyl group at 0 deg.C]Piperidin-1-yl radical]Add NaBH portionwise to a solution of Ethan-1-one (0.70 g, 2.12 mmol) in MeOH (5 mL)₄(0.12 g, 3.18 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was washed with saturated NH at 0 deg.C₄Aqueous Cl (30 mL), extracted with EA (3X 50 mL), over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (3/1) to give 1- (4- ((4, 5-dichloro-2-methoxyphenyl) (hydroxy) methyl) piperidin-1-yl) ethanone (0.46 g, 66%) as a yellow oil as C₁₅H₁₉Cl₂NO₃ [M + H]⁺Calculated lcms (esi): 332, 334 (3: 2), found 332, 334 (3: 2).

Step c:

to a stirred mixture of 1- [4- [ (4, 5-dichloro-2-methoxyphenyl) (hydroxy) methyl group at 0 deg.C]Piperidin-1-yl radical ]Ethan-1-one (0.46 g, 1.38 mmol) in DCM (5 mL) was added PBr dropwise₃(0.75 g, 2.77 mmol). After stirring at 0 ℃ for 1 hour, the reaction solution was quenched with water (30 mL) at 0 ℃ and extracted with EA (4X 10 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (2/1) to give 1- (4- (bromo (4, 5-dichloro-2-methoxyphenyl) methyl) piperidin-1-yl) ethanone (50 mg, 10%) as a yellow oil C₁₅H₁₈BrCl₂NO₂ [M + H]⁺Calculated lcms (esi): 394, 396, 398 (2: 3: 1), found 394, 396, 398 (2: 3: 1);¹H NMR (300 MHz, CD₃OD) δ 7.57 (s, 1H), 7.15 (s, 1H), 5.14 (dd, J = 9.5, 2.4 Hz, 1H), 3.99-3.90 (m, 1H), 3.85 (s, 3H), 3.84-3.80 (m, 1H), 3.18-2.91 (m, 1H), 2.69-2.45 (m, 1H), 2.38-2.17 (m, 2H), 2.05 (d, J = 15.0 Hz, 3H), 1.43-1.15 (m, 3H)。

step d:

to a solution of 1- (4- (bromo (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) ethanone (50 mg, 0.13 mmol) in DMF (3 mL) at room temperature was added NaN₃(26 mg, 0.40 mmol). The reaction mixture was warmed to 100 ℃ and stirred for 8 hours. After cooling to room temperature, the resulting mixture was diluted with water (20 mL) and extracted with EA (3X 25 mL). The combined organic layers were washed with brine (3X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated to one-quarter volume under reduced pressure. The residue was used without further purification in the next step: c ₁₅H₁₈Cl₂N₄O₂ [M + H]⁺Lcms (esi) calculated value of (a): 357, 359 (3: 2), found 357, 359 (3: 2).

Step e:

to 1- [4- [ azido (4, 5-dichloro-2-methoxyphenyl) methyl at room temperature]Piperidin-1-yl radical]To a solution of ethan-1-one (0.10 g, 0.28 mmol) in THF (4 mL) was added PPh₃(0.15 g, 0.56 mmol) and NH₃·H₂O (1 mL, 28% in H₂O). The reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 29% aqueous ACN (plus 0.05% TFA) to give 1- (4- (amino (4, 5-dichloro-2-methoxyphenyl) methyl) piperidin-1-yl) ethanone (30 mg, 71% total of two steps): C as a pale yellow solid₁₅H₂₀Cl₂N₂O₂ [M + H]⁺Calculated lcms (esi): 331, 333 (3: 2), found 331, 333 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.47 (d, J = 1.9 Hz, 1H), 7.16 (d, J = 1.4 Hz, 1H), 4.60-4.40 (m, 1H), 3.99-3.82 (m, 2H), 3.81 (s, 3H), 3.17-2.89 (m, 1H), 2.66-2.44 (m, 1H), 2.15-1.78 (m, 5H), 1.43-1.03 (m, 3H)。

example 5 intermediate 5 (N- ((2- (allyloxy) -4, 5-dichlorophenyl) (piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide)

Step a:

to a stirred mixture of (4, 5-dichloro-2-hydroxyphenyl) (piperidin-4-yl) methanone (17 g, 62.27 mmol) and Et at 0 deg.C₃Boc was added portionwise to a solution of N (31.44 g, 0.31 mol) in DCM (150 mL)₂O (14.90 g, 68.21 mmol). The reaction solution was warmed to room temperature and stirred at room temperature for 4 hours. The resulting solution was quenched with water (300 mL) at room temperature and extracted with EA (3X 300 mL). The combined organic layers were washed with brine (2X 100 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used without further purification in the subsequent step: c₁₇H₂₁Cl₂NO₄ [M + H]⁺Calculated lcms (esi): 374, 376 (3: 2), found 374, 376 (3: 2).

Step b:

to a stirred solution of 4- (4, 5-dichloro-2-hydroxybenzoyl) piperidine-1-carboxylic acid under nitrogen at room temperatureTert-butyl ester (crude) and K₂CO₃(33.20 g, 0.24 mmol) to a mixture in DMF (200 mL) was added allyl bromide (14.48 g, 0.12 mmol) dropwise. The reaction mixture was warmed to 40 ℃ and stirred for 12 hours. The resulting mixture was diluted with water (500 mL) and extracted with EA (2X 500 mL). The combined organic layers were washed with brine (2X 100 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with PE/EA (5/1) to give tert-butyl 4- (2- (allyloxy) -4, 5-dichlorobenzoyl) piperidine-1-carboxylate (15.40 g, 64% in two steps in total) as a pale yellow solid, C₂₀H₂₅Cl₂NO₄ [M + H]⁺Calculated lcms (esi): 414, 416 (3: 2), found 414, 416 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.69 (s, 1H), 7.07 (s, 1H), 6.16-6.00 (m, 1H), 5.55-5.36 (m, 2H), 4.62 (d, J = 5.7 Hz, 2H), 4.18-4.08 (m, 2H), 3.41-3.32 (m, 1H), 2.94-2.74 (m, 2H), 1.93-1.81 (m, 2H), 1.68-1.54 (m, 2H), 1.54 (s, 9H)。

step c:

to a stirred mixture of 4- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl at room temperature under nitrogen atmosphere]Piperidine-1-carboxylic acid tert-butyl ester (8.80 g, 21.24 mmol) and Ti (OEt) ₄ (21.51 g, 94.30 mmol) to a mixture in THF (50 mL) was added 2-methylpropane-2-sulfinamide (3.86 g, 31.85 mmol) in portions. The reaction mixture was warmed to 70 ℃ and stirred under nitrogen for 16 hours. The resulting mixture was quenched with water (200 mL) at room temperature. A solid was formed and filtered. The filtrate was extracted with EA (3X 200 mL). The combined organic layers were washed with brine (2X 100 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to crude tert-butyl 4- ((2- (allyloxy) -4, 5-dichlorophenyl) ((tert-butylsulfinyl) imino) methyl) piperidine-1-carboxylate. The crude product was used without further purification in the subsequent step: c₂₄H₃₄Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 517, 519 (3: 2), found 517, 519 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.16 (s, 1H), 6.95 (s, 1H), 6.05-5.95 (m, 1H), 5.43-5.26 (m, 2H), 4.56 (d, J = 5.8 Hz, 2H), 4.25-4.00 (m, 2H), 2.86-2.52 (m, 3H), 1.91-1.54 (m, 4H), 1.45 (s, 9H), 1.21 (s, 9H)。

step d:

to a solution of tert-butyl 4- ((2- (allyloxy) -4, 5-dichlorophenyl) ((tert-butylsulfinyl) imino) methyl) piperidine-1-carboxylate (crude) in MeOH (80 mL) under a nitrogen atmosphere at 0 deg.C was added NaBH in portions₄(1.21 g, 31.86 mmol). After addition, the reaction mixture was allowed to warm to room temperature and stirred under nitrogen for 2 hours. The resulting mixture was quenched with water (150 mL) at 0 ℃ and extracted with EA (3X 100 mL). The combined organic layers were washed with water (2X 50 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 45% aqueous ACN (plus 0.05% TFA) to give tert-butyl 4- ((2- (allyloxy) -4, 5-dichlorophenyl) (1, 1-dimethylethylenesulfonamido) methyl) piperidine-1-carboxylate (6.58 g, 60% total of two steps): C₂₄H₃₆Cl₂N₂O₄S [M + H]⁺Lcms (esi) calculated value of (a): 519, 521 (3: 2), found 519, 521 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.51 (s, 1H), 7.15 (s, 1H), 6.19-6.03 (m, 1H), 5.52-5.29 (m, 2H), 4.67-4.58 (m, 2H), 4.30 (d, J = 9.1 Hz, 1H), 4.04 (dd, J = 35.2, 13.5 Hz, 2H), 2.84-2.50 (m, 2H), 2.14-1.87 (m, 2H), 1.46 (s, 9H), 1.30-1.05 (m, 3H), 1.23 (s, 9H)。

step e:

to a stirred solution of tert-butyl 4- ((2- (allyloxy) -4, 5-dichlorophenyl) (1, 1-dimethylethylenesulfonamido) methyl) piperidine-1-carboxylate (6.58 g, 12.68 mmol) in DCM (100 mL) was added TFA (20 mL) dropwise at room temperature. The reaction solution was stirred at room temperature for 1 hour. The resulting solution was diluted with water (200 mL). At 0 deg.C, with saturated NaHCO₃The aqueous solution adjusted the pH of the reaction system to 9. The aqueous layer was extracted with EA (3X 500 mL). The combined organic layers were washed with brine (2X 50 mL) and dried over anhydrous Na₂SO₄And (5) drying. Filtering, and collecting the filtrateConcentrating under reduced pressure. The residue was purified by reverse phase chromatography eluting with 35% aqueous ACN (plus 0.05% TFA) to afford the title compound as a pale yellow oilN- ((2- (allyloxy) -4, 5-dichlorophenyl) (piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (4.24 g, 80%): C ₁₉H₂₈Cl₂N₂O₂S [M + H]⁺Lcms (esi) calculated value of (a): 419, 421 (3: 2), found 419, 421 (3: 2);¹H NMR (300 MHz, DMSO-d ₆ + D₂O) δ 7.50 (s, 1H), 7.19 (s, 1H), 6.06-5.92 (m, 1H), 5.42-5.18 (m, 2H), 4.63-4.48 (d, J = 4.8 Hz, 2H), 4.47-4.34 (d, J =8.7 Hz, 1H), 3.38-3.14 (m, 2H), 2.84-2.65 (m, 2H), 2.20-2.05 (m, 1H), 1.96-1.82 (m, 1H), 1.42-1.18 (m, 3H), 0.97 (s, 9H)。

example 6 intermediate 6 (, (b)S)-N-((R) - (2- (allyloxy) -4, 5-dichlorophenyl) (piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide), Process A

Step a:

to a stirred mixture of tert-butyl 4- (2- (allyloxy) -4, 5-dichlorobenzoyl) piperidine-1-carboxylate (5.16 g, 12.45 mmol) and Ti (OEt) at room temperature under nitrogen at room temperature₄(8.52 g, 37.36 mmol) in THF (50 mL) was added (S) 2-methylpropane-2-sulfinamide (1.67 g, 13.70 mmol). The reaction solution was warmed to 70 ℃ and stirred for 36 hours. After cooling to room temperature, the resulting solution was quenched with water (300 mL) at room temperature. A solid was formed and filtered. The filtrate was extracted with EA (2X 500 mL). The combined organic layers were washed with brine (2X 100 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was dried in a vacuum oven to give (A) as a pale yellow solidS) Tert-butyl (6.00 g, 93%) 4- ((2- (allyloxy) -4, 5-dichlorophenyl) ((tert-butylsulfinyl) imino) methyl) piperidine-1-carboxylate C₂₄H₃₄Cl₂N₂O₄S [M + H]⁺LCMS (E) of (A)SI) calculated values: 517, 519 (3: 2), found 517, 519 (3: 2);¹H NMR (300 MHz, CDCl₃) δ 7.28 (s, 1H), 6.97 (s, 1H), 6.06-5.94 (m, 1H), 5.46-5.26 (m, 2H), 4.58 (d, J = 5.7 Hz, 2H), 4.23-4.01 (m, 2H), 3.81-3.62 (m, 1H), 2.84-2.57 (m, 2H), 1.93-1.81 (m, 2H), 1.68-1.54 (m, 2H), 1.46 (s, 9H), 1.22 (s, 9H)。

step b:

under nitrogen atmosphere at-65 deg.C for 30 min: ( S) Tert-butyl-4- ((2- (allyloxy) -4, 5-dichlorophenyl) ((tert-butylsulfinyl) imino) methyl) piperidine-1-carboxylate (1.50 g, 2.90 mmol) in toluene (10 mL) was added DIBAL-H (4.35 mL, 4.35 mmol, 1M in toluene) dropwise. After the addition, the reaction solution was stirred at-65 ℃ for 3 hours under nitrogen atmosphere. The resulting solution was quenched with water (20 mL) at-65 ℃ and then diluted with saturated aqueous sodium potassium tartrate (200 mL). The aqueous layer was extracted with EA (3X 100 mL). The combined organic layers were washed with water (2X 50 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluted with 45% aqueous ACN (plus 0.05% TFA) to give 4- (a) as a yellow oilR) - (2- (allyloxy) -4, 5-dichlorophenyl) ((S) -1, 1-Dimethylethylsulfenamide) methyl) piperidine-1-carboxylic acid tert-butyl ester (0.78 g, 52%): C₂₄H₃₆Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 519, 521 (3: 2), found 519, 521 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.23 (s, 1H), 6.96 (s, 1H), 6.10-5.92 (m, 1H), 5.46-5.31 (m, 2H), 4.57 (d, J = 5.8 Hz, 2H), 4.50-4.37 (m, 1H), 4.28-4.04 (m, 2H), 3.84-3.64 (m, 1H), 2.71-2.49 (m, 2H), 2.01-1.81 (m, 2H), 1.47 (s, 9H), 1.49-1.22 (m, 3H), 1.17 (s, 9H)。

step c:

to stirred 4- (C) at room temperatureR) - (2- (allyloxy) -4, 5-dichlorophenyl) ((S) -1, 1-Dimethylethylsulfonamido) methyl) piperidine-1-carboxylic acid tert-butyl ester (16.00 g, 30.80 mmol) in DCM (120 mL) was added TFA (30 mL) dropwise. The reaction solution was allowed to stand at room temperature Stirred for 1 hour. The resulting solution was diluted with water (200 mL). At 0 deg.C, with saturated NaHCO₃The aqueous solution adjusted the pH of the reaction system to 8. The aqueous layer was extracted with EA (3X 500 mL). The combined organic layers were washed with brine (2X 50 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with a concentration of 10 mmol/LNH₄HCO₃Is eluted with 35% aqueous ACN to give (a) as a yellow oilS)-N-((R) - (2- (allyloxy) -4, 5-dichlorophenyl) (piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (7.00 g, 46%): C₁₉H₂₈Cl₂N₂O₂S [M + H]⁺Calculated lcms (esi): 419, 421 (3: 2), found 419, 421 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.25 (s, 1H), 6.98 (s, 1H), 6.10-5.97 (m, 1H), 5.46-5.31 (m, 2H), 4.57 (d, J = 5.8 Hz, 2H), 4.49-4.37 (m, 1H), 4.88-3.95 (m, 1H), 3.42-3.24 (m, 2H), 2.81-2.67 (m, 2H), 2.21-2.09 (m, 1H), 2.04-1.97 (m, 1H), 1.65-1.42 (m, 3H), 1.17 (s, 9H)。

intermediate 6 (, (S)-N-((R) - (2- (allyloxy) -4, 5-dichlorophenyl) (piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide), method B

Step a:

to a stirred solution of 3, 4-dichlorophenol (100.00 g, 613.49 mmol) in DCM (1000 mL) was added Br dropwise under a nitrogen atmosphere at 0 deg.C₂(98.04 g, 613.49 mmol). The reaction solution was stirred at room temperature under nitrogen atmosphere for 16 hours. At 0 deg.C, the reaction was saturated with Na₂S₂O₃Aqueous solution (500 mL) was quenched. The resulting mixture was extracted with EA (6X 400 mL). The combined organic layers were washed with brine (2X 400 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 2-bromo-4, 5-dichlorophenol as a yellow oil. The crude product was purified without further purificationAnd is directly used for the subsequent steps:¹H NMR (400 MHz, CDCl₃) δ 7.57 (s, 1H), 7.15 (s, 1H)。

step b:

to a stirred mixture of 2-bromo-4, 5-dichlorophenol (50.00 g, 206.71 mmol) and K at room temperature under a nitrogen atmosphere₂CO₃ (57.14 g, 413.41 mmol) in DMF (500 mL) was added 3-bromoprop-1-ene (37.51 g, 310.06 mmol) dropwise. The reaction mixture was stirred under nitrogen at 40 ℃ for 16 hours. The resulting mixture was diluted with water (1.5L) and extracted with EA (3X 0.5L). The combined organic layers were washed with brine (4X 0.5L) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE to give 1-bromo-4, 5-dichloro-2- (prop-2-en-1-yloxy) benzene (40.00 g, 61%) as a pale yellow oil:¹H NMR (400 MHz, CDCl₃) δ 7.65 (s, 1H), 6.98 (s, 1H), 6.12-6.06 (m, 1H), 5.60-5.29 (m, 2H), 4.69-4.57 (m, 2H)。

step c:

to a stirred solution of 1-bromo-4, 5-dichloro-2- (prop-2-en-1-yloxy) benzene (30.00 g, 106.39 mmol) in THF (800 mL) was added dropwise over 30 minutes at-15 deg.C under a nitrogen atmospherei-PrMgCl-LiCl (125 mL, 159.59 mmol, 1.3M THF solution). The resulting mixture was stirred at-15 ℃ for an additional 0.5 hours under nitrogen. To the resulting solution was added 4- [ [ (C) at-15 ℃ under nitrogen atmosphere S) -2-methylpropan-2-sulfinyl]Imino radical]Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester (33.67 g, 106.39 mmol). After the addition, the reaction mixture was stirred at-15 ℃ for 2 hours. The reaction was quenched with saturated NH at-15 deg.C₄Aqueous Cl (100 mL) was quenched and extracted with EA (3X 500 mL). The combined organic layers were washed with brine (3X 100 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography, eluting with PE/EA (1/2), to obtain 4- [ (R) ((R) ()) as an off-white solidR) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester (34.00 g, 58%): C₂₄H₃₆Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 519, 521 (3: 2), found 519, 521 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.44 (s, 1H), 7.17 (s, 1H), 6.18-6.03 (m, 1H), 5.49-5.31 (m, 2H), 4.62 (d, J = 5.2 Hz, 2H), 4.52 (d, J =8.8 Hz, 1H), 4.13 (t, J = 10.0 Hz, 1H), 4.01 (d, J = 13.4 Hz, 1H), 2.70 (d, J = 35.8 Hz, 2H), 2.12 (d, J = 13.6 Hz, 1H), 2.01-1.88 (m, 1H), 1.46 (s, 9H), 1.36-1.19 (m, 3H), 1.13 (d, J = 1.4 Hz, 9H)。

step d:

stirring 4- [ (ii) at room temperatureR) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]To a mixture of tert-butyl piperidine-1-carboxylate (5.70 g, 10.97 mmol) in DCM (40 mL) was added TFA (10 mL) dropwise. The reaction solution was stirred at room temperature for 1 hour. The mixture was washed with saturated NaHCO at 0 deg.C₃The aqueous solution was neutralized to pH 9. The resulting mixture was extracted with EA (2X 100 mL). The combined organic layers were washed with brine (2X 100 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography with a solution having 10 mmol/L NH₄HCO₃Eluting with 40% aqueous ACN solution to obtain (A), (B) and (C) as yellow solidS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide (3.50 g, 68%) C₁₉H₂₈Cl₂N₂O₂S [M + H]⁺Lcms (esi) calculated value of (a): 419, 421 (3: 2), found 419, 421 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.25 (s, 1H), 6.98 (s, 1H), 6.10-5.97 (m, 1H), 5.46-5.31 (m, 2H), 4.57 (d, J = 5.8 Hz, 2H), 4.49-4.37 (m, 1H), 4.88-3.95 (m, 1H), 3.42-3.24 (m, 2H), 2.81-2.67 (m, 2H), 2.21-2.09 (m, 1H), 2.04-1.97 (m, 1H), 1.65-1.42 (m, 3H), 1.17 (s, 9H)。

example 7 intermediate 7 (b)N- ((2-hydroxynaphthalen-1-yl) (pyridin-4-yl) methyl) acetamide)

A, step a:

to a stirred mixture of naphthalene-2-ol (3.50 g, 24.28 mmol), acetamide (1.72 g, 29.13 mmol) and pyridine-4-carbaldehyde (2.60 g, 24.28 mmol) was added portionwise AlCl under nitrogen at 110 deg.C₃(0.49 g, 3.64 mmol). The reaction mixture was stirred at 110 ℃ for 8 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was quenched with water (60 mL). The aqueous layer was extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with DCM/MeOH (8/1) to give a pale green solidN- [ (2-Hydroxynaphthalen-1-yl) (pyridin-4-yl) methyl ]Acetamide (1.00 g, 14%): C₁₈H₁₆N₂O₂ [M + H]⁺Lcms (esi) calculated value of (a): 293, found 293;¹H NMR (400 MHz, CD₃OD) δ 8.39 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.6 Hz, 1H), 7.87 (t, J = 9.0 Hz, 2H), 7.54 (t, J = 7.7 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.29-7.24 (m, 3H), 7.21 (d, J = 8.6 Hz, 1H), 2.10 (s, 3H)。

example 8 intermediate 8 (C)N- ((2- (allyloxy) -4, 5-dichlorophenyl) (piperidin-4-yl) methyl) -2,2, 2-trifluoroacetamide trifluoroacetic acid)

Step a:

to a stirred solution of tert-butyl 4- ((2- (allyloxy) -4, 5-dichlorophenyl) (1, 1-dimethylethylenesulfonamido) methyl) piperidine-1-carboxylate (0.50 g, 0.96 mmol) in 1, 4-dioxane (5 mL) was added aqueous HCl (6 mL) at room temperatureN0.5 mL). The reaction solution was stirred at room temperature for 1 hour. The resulting solution was taken up in saturated NaHCO₃Aqueous solutionNeutralized to pH 7 and then concentrated under reduced pressure. The residue was purified by reverse phase chromatography using a column containing 20 mmol/L NH₄HCO₃Was eluted with 60% aqueous ACN solution to give tert-butyl 4- ((2- (allyloxy) -4, 5-dichlorophenyl) (amino) methyl) piperidine-1-carboxylate (0.40 g, 90%) C as a brown oil₂₀H₂₈Cl₂N₂O₃ [M + H]⁺Calculated lcms (esi): 415, 417 (3: 2), found 415, 417 (3: 2).

Step b:

to a stirred mixture of tert-butyl 4- ((2- (allyloxy) -4, 5-dichlorophenyl) (amino) methyl) piperidine-1-carboxylate (0.11 g, 0.27 mmol) and Et at 0 deg.C₃A solution of N (54 mg, 0.53 mmol) in DCM (3 mL) was added TFAA (61 mg, 0.29 mmol) dropwise. The reaction solution was stirred at 0 ℃ for 0.5 hour. The reaction solution was diluted with DCM (50 mL). The solution was washed with brine (2X 20 mL) over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl 4- ((2- (allyloxy) -4, 5-dichlorophenyl) (2,2, 2-trifluoroacetamido) methyl) piperidine-1-carboxylate (0.13 g, 95%) as a yellow solid as C₂₂H₂₇Cl₂F₃N₂O₄ [M + H]⁺Lcms (esi) calculated value of (a): 511, 513 (3: 2), found 511, 513 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.25 (s, 1H), 7.02 (s, 1H), 6.11-5.99 (m, 1H), 5.47-5.38 (m, 2H), 4.78 (t, J = 12.0 Hz, 1H), 4.86-4.57 (m, 2H), 4.31-3.93 (m, 2H), 2.75-2.48 (m, 2H), 2.01-1.91 (m, 1H), 1.83-1.72 (m, 1H), 1.46 (s, 9H), 1.49-1.22 (m, 3H)。

step c:

to a solution of tert-butyl 4- ((2- (allyloxy) -4, 5-dichlorophenyl) (2,2, 2-trifluoroacetamido) methyl) piperidine-1-carboxylate (0.13 g, 0.25 mmol) in DCM (3 mL) was added TFA (3 mL) dropwise at room temperature. The reaction solution was stirred at room temperature for 0.5 hour. Concentrating the reaction solution under reduced pressure to obtain the product in the form of yellow solidN- ((2- (allyloxy) -4, 5-dichlorophenyl) (piperidin-4-yl) methyl) -2,2, 2-trifluoroacetamide trifluoroacetic acid (0.10 g, 90%): C₁₇H₁₉Cl₂F₃N₂O₂ [M + H]⁺Calculated lcms (esi): 411, 413 (3: 2), found 411, 413 (3: 2).

EXAMPLE 9 intermediate 9 (1- (allyloxy) -2-bromo-3, 4, 5-trichlorobenzene)

Step a:

to a stirred solution of (3,4, 5-trichlorophenyl) boronic acid (5.00 g, 22.20 mol) in THF (15 mL) at room temperature was added H₂O₂(1.51 g, 44.39 mmol, 30%) and NaOH (1.78 g, 44.39 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction was incubated with saturated Na at room temperature ₂SO₃Aqueous solution (10 mL) was quenched. The mixture was washed with aqueous HCl (1)N) Acidifying to pH 3. The resulting mixture was extracted with EA (3X 80 mL). The combined organic layers were washed with brine (2X 80 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (5/1) to give 3,4, 5-trichlorophenol (4.30 g, 95%) as a pale yellow solid:¹ H NMR (300 MHz, CDCl₃) δ 6.92 (s, 2H)。

step b:

to a stirred solution of 3,4, 5-trichlorophenol (4.60 g, 23.30 mol) in AcOH (20 mL) was added dropwise Br under argon at room temperature₂ (3.70 g, 23.15 mol). After stirring for 6 hours, the reaction was saturated with Na₂SO₃Aqueous solution (80 mL) was quenched and extracted with EA (3X 80 mL). The combined organic layers were washed with brine (3X 80 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluting with PE/EA (20/1), to give 2-bromo-3, 4, 5-trichlorophenol (2.40 g, 37%) as an off-white solid:¹ H NMR (400 MHz, DMSO-d ₆) δ 11.43 (s, 1H), 7.15 (s, 1H)。

step c:

to a stirred mixture of 2-bromo-3, 4, 5-trichlorophenol (2.40 g, 8.69 mmol) and K at room temperature₂CO₃(2.40 g, 17.37 mmol) to a solution in DMF (15 mL) was added allyl bromide (1.26 g, 10.42 mmol). The reaction was allowed to warm to 50 ℃ and stirred for 1 hour. The reaction mixture was diluted with EA (80 mL) and water (80 mL) and then extracted with EA (3X 80 mL). The combined organic layers were washed with brine (6X 80 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with PE/EA (20/1) to give 2-bromo-3, 4, 5-trichloro-1- (prop-2-en-1-yloxy) benzene (1.80 g, 66%) as a pale yellow oil.

Example 10 intermediate 10 (, (b)S) -4- (((tert-butylsulfinyl) imino) methyl) piperidine-1-carboxylic acid tert-butyl ester)

Step a:

to a stirred mixture of tert-butyl 4-formylpiperidine-1-carboxylate (50.00 g, 0.23 mol) and (C) (b) under nitrogen at room temperatureS) (iii) -2-methylpropane-2-sulfinamide (43.00 g, 0.35 mmol) in THF (300 mL) Ti (OEt)₄(187.00 g, 0.82 mol). The reaction solution was stirred at room temperature under nitrogen atmosphere for 4 hours. The resulting solution was treated with saturated NH at room temperature₄Aqueous Cl (200 mL) was quenched and extracted with EA (3X 300 mL). The combined organic layers were washed with brine (3X 200 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give (A) as an off-white solidS) -tert-butyl 4- (((tert-butylsulfinyl) imino) methyl) piperidine-1-carboxylate (67 g, 81%): C₁₅H₂₈N₂O₃S [M + H]⁺Calculated lcms (esi): 317, measured value 317;¹H NMR (300 MHz, CDCl₃) δ 8.01 (d, J = 3.9 Hz, 1H), 4.09 (d, J = 13.4 Hz, 2H), 2.97-2.82 (m, 2H), 2.62 (m, 1H), 1.90 (dd, J = 13.4, 3.6 Hz, 2H), 1.71-1.43 (m, 2H), 1.47 (s, 9H), 1.20 (s, 9H)。

EXAMPLE 11 intermediate 11 (tert-butyl 4- (((tert-butylsulfinyl) imino) methyl) piperidine-1-carboxylate)

A, step a:

to a stirred solution of tert-butyl 4-formylpiperidine-1-carboxylate (20.00 g, 93.90 mmol) and 2-methylpropane-2-sulfinamide (17.00 g, 0.14 mol) in THF (300 mL) at room temperature under a nitrogen atmosphere was added Ti (OEt) dropwise₄(50.00 g, 0.18 mmol). The reaction solution was stirred at room temperature for 4 hours under a nitrogen atmosphere. The resulting solution was saturated with NH at room temperature₄Aqueous Cl (200 mL) was quenched and extracted with EA (3X 500 mL). The combined organic layers were washed with brine (2X 200 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl 4- (((tert-butylsulfinyl) imino) methyl) piperidine-1-carboxylate (24.00 g, 80%) as a pale yellow solid₁₅H₂₈N₂O₃S [M + H]⁺Calculated lcms (esi): 317, measured value 317.

Example 12 intermediate 12 (, (b)S)-N- ((1- ((R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl) piperidin-4-yl) methylene) -2-methylpropane-2-sulfinamide)

Step a:

to a stirred solution of tert-butyl 4-formylpiperidine-1-carboxylate (9.00 g, 42.20 mmol) in DCM (60 mL) was added TFA (30 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was dried under reduced pressure. The crude product was used without further purification in the subsequent steps: c ₆H₁₁NO [M + H]⁺Lcms (esi) calculated value of (a): 114, found value 114.

Step b:

stirred (4) at room temperature under nitrogen atmosphereR) -2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid (8.37 g, 5)7.27 mmol) and HATU (21.77 g, 57.26 mmol) in DMF (150 mL) was added piperidine-4-carbaldehyde (5.40 g, 47.72 mmol) and Et₃N (72.43 g, 0.72 mol). The resulting mixture was stirred at room temperature under nitrogen for 2 hours. The reaction was quenched with water (100 mL) at room temperature and extracted with EA (3X 200 mL). The combined organic layers were washed with brine (3X 100 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used without further purification in the subsequent steps: c₁₂H₁₉NO₄ [M + H]⁺Calculated lcms (esi): 242, found value 242.

Step c:

to stirred 1- [ (4) at room temperature under nitrogen atmosphereR) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidine-4-carbaldehyde (4.30 g, 17.82 mmol) and (CS) (iii) -2-methylpropane-2-sulfinamide (3.24 g, 26.73 mmol) in THF (40 mL) Ti (OEt)₄(12.20 g, 53.48 mmol). The resulting mixture was stirred at room temperature under nitrogen for 4 hours. The reaction was quenched with water (150 mL) at room temperature. The resulting mixture was extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography, eluting with PE/EA (1: 3) to obtain (B) as light yellow oilS)-N-((1-((R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl) piperidin-4-yl) methylene) -2-methylpropane-2-sulfinamide (4.37 g, 71%): C₁₆H₂₈N₂O₄S [M + H]⁺Lcms (esi) calculated value of (a): 345, found 345.¹H NMR (400 MHz, DMSO-d ₆) δ 7.92 (d, J = 3.9 Hz, 1H), 4.91-4.77 (m, 1H), 4.36-4.12 (m, 2H), 4.11-3.94 (m, 1H), 3.16 (dt, J = 25.1, 12.4 Hz, 1H), 2.91-2.73 (m, 2H), 1.90 (d, J = 14.6 Hz, 2H), 1.56-1.40 (m, 1H), 1.39-1.25 (m, 8H), 1.11 (d, J = 1.3 Hz, 9H)。

EXAMPLE 13 intermediate 13 (2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid)

Step a:

to a stirred solution of KOH (2.10 g, 37.42 mmol) in H at room temperature₂Methyl 2, 2-dimethyl-1, 3-dioxolane-4-carboxylate (3.00 g, 18.73 mmol) was added portionwise to a mixture of O (9 mL) and EtOH (18 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was taken up in 10% H₃PO₄The aqueous solution was acidified to pH 4. The resulting mixture was extracted with EA (3X 40 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid (1.80 g, 65%) as a colorless oil:¹H NMR (400 MHz, DMSO-d ₆) δ 12.81 (s, 1H), 4.58-4.50 (m, 1H), 4.17 (t, J = 7.9 Hz, 1H), 4.05-3.89 (m, 1H), 1.37 (s, 3H), 1.30 (s, 3H)。

example 14 intermediate 14 (, (b)R) -2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid)

Step a:

to a stirred solution of KOH (3.50 g, 62.38 mmol) in H at room temperature ₂To a solution of O (5 mL) and EtOH (10 mL) was added portionwise (4)R) Methyl 2, 2-dimethyl-1, 3-dioxolane-4-carboxylate (5.00 g, 31.22 mmol). The reaction mixture was stirred at room temperature for an additional 2 hours. Subjecting the mixture to hydrogenation with hydrogen₂Diluted O (10 mL) with 10% H₃PO₄The aqueous solution was acidified to pH 3. The resulting mixture was extracted with EA (3X 60 mL). The combined organic layers were washed with brine (3X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give (4) as a pale yellow oilR) -2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid (3.00 g, 66%): C₆H₁₀O₄ [M - H]⁺LCMS (ESI)) Calculated values: 145, found 145;¹H NMR (400 MHz, DMSO-d ₆) δ 12.80 (br, 1H), 4.59-4.50 (m, 1H), 4.27-4.10 (m, 1H), 4.00-3.91 (m, 1H), 1.45 (s, 3H), 1.38 (s, 3H)。

EXAMPLE 15 intermediate 15 (1, 2-dichloro-3-iodo-4-methoxybenzene)

Step a:

to stirred 3, 4-dichlorophenol (50.00 g, 306.75 mmol), DMAP (74.95 g, 613.50 mmol) and Et at room temperature under a nitrogen atmosphere₃A solution of N (62.08 g, 613.50 mmol) in DCM (500 mL) was added dropwise diethyl carbamoyl chloride (62.39 g, 460.12 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The resulting mixture was diluted with water (300 mL) and extracted with EA (3X 500 mL) at room temperature. The combined organic layers were washed with brine (2X 200 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (40/1) to give a yellow oilN,N3, 4-Dichlorophenyl-diethyl-carbamate (72.00 g, 80%): C₁₁H₁₃Cl₂NO₂ [M + H]⁺Calculated lcms (esi): 262, 264 (3: 2), found 262, 264 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.42 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 2.7 Hz, 1H), 7.03 (dd, J = 8.8, 2.7 Hz, 1H), 3.42 (dq, J = 14.2, 7.2 Hz, 4H), 1.24 (dt, J = 14.8, 7.2 Hz, 6H)。

step b:

to a solution of diethylpropylamine (DIPA, 42.46 g, 419.64 mmol) in THF (400 mL) was added dropwise over 0.5 h at-78 deg.C under a nitrogen atmospherenBuLi (29.32 g, 457.79 mmol, 2.5M in hexane). After stirring at-78 ℃ for 20 minutes, the resulting solution was added dropwise at-78 ℃ over 20 minutesN,NDissolution of 3, 4-dichlorophenyl diethylcarbamate (100.00 g, 381.49 mmol) in THF (100 mL)And (4) liquid. After addition, the resulting mixture was stirred at-78 ℃ for an additional 0.5 hours under nitrogen atmosphere. Dropwise adding I to the mixture at-78 ℃ over 0.5 hour₂(101.67 g, 400.56 mmol) in THF (50 mL). The resulting mixture was stirred at-78 ℃ for an additional 2 hours. The resulting mixture was taken up with saturated Na at-78 deg.C₂SO₃Aqueous solution (300 mL) was quenched and extracted with EA (3X 500 mL). The combined organic layers were washed with brine (2X 200 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EA (40/1) to give an off-white solidN,N3, 4-dichloro-2-iodophenyl (117.00 g, 79%): C₁₁H₁₂Cl₂INO₂ [M + H]⁺Calculated lcms (esi): 388, 390 (3: 2), found 388, 390 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.48 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 8.7 Hz, 1H), 3.55 (q, J = 7.1 Hz, 2H), 3.42 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H)。

step c:

at 0 ℃ with stirringN,N3, 4-dichloro-2-iodophenyl-diethyl-carbamate (65.80 g, 169.58 mmol) in MeOH (100 mL) was added NaOH (67.82 g, 1695.75 mmol) in H₂Solution in O (200 mL). The resulting mixture was warmed to 50 ℃ and stirred for 10 hours. The pH of the solution was adjusted with aqueous HCl (1)N) Adjusted to 6-7. The reaction was diluted with water (400 mL) and extracted with EA (3X 400 mL) at room temperature. The combined organic layers were washed with brine (3X 100 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (40/1) to give 3, 4-dichloro-2-iodophenol (47.00 g, 96%) as a yellow oil:¹H NMR (400 MHz, CDCl₃) δ 7.36 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.09 (s, 1H)。

step d:

in a nitrogen atmosphereNext, to a stirred solution of 3, 4-dichloro-2-iodophenol (100.00 g, 346.15 mmol) in DMF (300 mL) at room temperature was added CH₃I (73.70 g, 519.23 mmol) and K ₂CO₃ (95.68 g, 692.31 mmol). The resulting mixture was stirred at room temperature under nitrogen for 5 hours. The reaction was diluted with water (500 mL) and extracted with EA (3X 600 mL) at room temperature. The combined organic layers were washed with brine (3X 1000 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (20/1) to give 1, 2-dichloro-3-iodo-4-methoxybenzene (88.00 g, 84%) as an off white solid:¹H NMR (400 MHz, CDCl₃) δ 7.44 (d, J = 8.9 Hz, 1H), 6.69 (d, J = 8.8 Hz, 1H), 3.91 (s, 3H)。

EXAMPLE 16 intermediate 16 (1- (allyloxy) -3, 4-dichloro-2-iodobenzene)

Step a:

to a stirred mixture of 3, 4-dichloro-2-iodophenol (25.00 g, 86.54 mmol) and K at room temperature₂CO₃(35.88 g, 259.61 mmol) in DMF (100 mL) was added 3-bromoprop-1-ene (15.70 g, 129.81 mmol) dropwise. The resulting mixture was warmed to 40 ℃ and stirred under nitrogen for 4 hours. After cooling to room temperature, the resulting mixture was diluted with water (300 mL) at room temperature and extracted with EA (3X 500 mL). The combined organic layers were washed with brine (3X 500 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (5/1) to give 1, 2-dichloro-3-iodo-4- (prop-2-en-1-yloxy) benzene as a yellow solid (16.00 g, 50%): ¹H NMR (400 MHz, CD₃OD) δ 7.49 (d, J = 8.9 Hz, 1H), 6.88 (d, J = 8.9 Hz, 1H), 6.17-6.00 (m, 1H), 5.54 (dt, J = 17.3, 1.7 Hz, 1H), 5.31 (dt, J = 10.7, 1.7 Hz, 1H), 4.65 (dd, J = 4.0, 2.3 Hz, 2H)。

EXAMPLE 17 intermediate 17 (4- (1- (4, 5-dichloro-2-methoxyphenyl) vinyl) piperidine-1-carboxylic acid tert-butyl ester)

A, step a:

to a stirred solution of methyltriphenylphosphonium bromide (1.10 g, 3.09 mmol) in THF (15 mL) under a nitrogen atmosphere at 0 deg.C was added NaH (0.12 g, 3.09 mmol, 60% in mineral oil) in portions. The reaction mixture was allowed to warm to room temperature and stirred for 15 minutes. Then adding 4- [ (4, 5-dichloro-2-methoxyphenyl) carbonyl]A solution of tert-butyl piperidine-1-carboxylate (0.80 g, 2.06 mmol) in THF (3 mL). The reaction mixture was stirred at room temperature for an additional 2 hours under nitrogen atmosphere. The resulting mixture was washed with saturated NH₄Aqueous Cl (40 mL) was quenched and extracted with EA (3X 10 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with PE/EA (5/1) to give 4- [1- (4, 5-dichloro-2-methoxyphenyl) vinyl group as a pale yellow oil]Piperidine-1-carboxylic acid tert-butyl ester (0.50 g, 63%): C₁₉H₂₅Cl₂NO₃ [M + H]⁺Calculated lcms (esi): 386, 388 (3: 2), found 386, 388 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.18 (s, 1H), 7.14 (s, 1H), 5.18 (s, 1H), 4.99 (s, 1H), 4.17-4.07 (m, 2H), 3.82 (s, 3H), 2.83-2.70 (s, 2H), 2.64-2.52 (m, 1H), 1.81-1.70 (m, 2H), 1.50-1.37 (s, 9H), 1.35-1.21 (m, 2H)。

example 18 intermediate 18 (, (b)S)-N-((R) - (3, 4-dichloro-2-fluoro-6-hydroxyphenyl) (piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide)

A, step a:

under nitrogen atmosphere, at-65 ℃ for 30 minutes to 5-bromo-1, 2-dichloro-3-fluorobenzene(4.00 g, 16.40 mmol) in THF (50 mL) was added dropwisei-PrMgCl. LiCl (25 mL, 32.80 mmol, 1.3M THF solution). After stirring for another 30 minutes, B (OMe) was added dropwise at-65 deg.C₃(2.56 g, 24.60 mmol) in THF (10 mL). After the addition, the reaction mixture was stirred at-65 ℃ for 30 minutes under nitrogen atmosphere. The resulting mixture was quenched with water (100 mL) at-65 ℃ and extracted with EA (2X 300 mL). The combined organic layers were washed with brine (2X 60 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with a solution containing 10 mmol/L NH₄HCO₃Eluted with 50% aqueous ACN to give (3, 4-dichloro-5-fluorophenyl) boronic acid (0.36 g, 94%) C as a yellow solid₆H₄BCl₂FO₂ [M - H]⁺Calculated lcms (esi): 207, 209 (3: 2), found 207, 209 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.66 (s, 1H), 7.47 (d, J = 9.2 Hz, 1H)。

step b:

to a stirred mixture of (3, 4-dichloro-5-fluorophenyl) boronic acid (3.60 g, 18.66 mmol) and KOH (4.19 g, 74.71 mmol, 4.00 equiv.) in MeOH (20 mL) at room temperature under an air atmosphere was added H dropwise₂O₂(2.54 g, 74.71 mmol, 30% aqueous solution). The reaction mixture was stirred at room temperature for 2 hours under an air atmosphere. The resulting mixture was treated with saturated NaHSO at room temperature ₃The aqueous solution (100 mL) was quenched and then the solution was acidified to pH 4 with citric acid. The resulting mixture was extracted with EA (2X 400 mL). The combined organic layers were washed with brine (2X 60 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (2/1) to give 3, 4-dichloro-5-fluorophenol (2.65 g, 70%) as a yellow solid:¹H NMR (400 MHz, CDCl₃) 6.83 (s, 1H), 6.64 (dd, J = 9.8, 2.8 Hz, 1H), 5.64 (s, 1H)。

step c:

to a stirred mixture of 3, 4-dichloro-5-fluorophenol (2.60 g, 14.36 mmol), Et, at room temperature under nitrogen at room temperature₃A solution of N (4.36 g, 43.09 mmol) and DMAP (3.51 g, 28.73 mmol) in DCM (20 mL) was added dropwise to diethyl carbamoyl chloride (2.33 g, 17.24 mmol). After stirring at room temperature for 2 hours under nitrogen atmosphere, the reaction solution was quenched with water (130 mL) at room temperature and extracted with EA (2X 200 mL). The combined organic layers were washed with brine (2X 50 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EA (6/1) to give an off-white solidN,N3, 4-dichloro-5-fluorophenyl (3.20 g, 70%): C₁₁H₁₂Cl₂FNO₂ [M + H]⁺Calculated lcms (esi): 280, 282 (3: 2), found 280, 282 (3: 2); ¹H NMR (400 MHz, CDCl₃) δ 7.15 (s, 1H), 7.00 (dd, J = 9.3, 2.6 Hz, 1H), 3.49-3.32 (m, 4H), 1.31-1.15 (m, 6H)。

Step d:

under nitrogen atmosphere at-65 ℃ for 10 minutesN,NTo a solution of 3, 4-dichloro-5-fluorophenyl (0.50 g, 1.79 mmol) in THF (10 mL) was added LDA (1.34 mL, 2.68 mmol, 2M in THF). After the addition, the reaction solution was stirred at-65 ℃ for 30 minutes, and then added dropwise at-65 ℃ for 10 minutes under a nitrogen atmosphere (S) A solution of tert-butyl 4- (((tert-butylsulfinyl) imino) methyl) piperidine-1-carboxylate (0.85 g, 2.68 mmol) in THF (5 mL). After stirring at-65 ℃ for an additional 1 hour under nitrogen, the resulting mixture was quenched with water (30 mL) at-65 ℃ and extracted with EA (2X 70 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. Filtering, and concentrating the filtrate under reduced pressure to obtain crude 4- (A)R) - (3, 4-dichloro-6- ((diethylcarbamoyl) oxy) -2-fluorophenyl) ((S) -1, 1-dimethylethylenesulfonamido) methyl) piperidine-1-carboxylic acid tert-butyl ester. The crude product was used without further purification in the subsequent steps: c₂₆H₄₀Cl₂FN₃O₅S [M + H]⁺Calculated lcms (esi): 596, 598 (3: 2), found 596, 598 (3: 2).

Step e:

to 4-(s) (at room temperature)R) - (3, 4-dichloro-6- ((diethylcarbamoyl) oxy) -2-fluorophenyl) (( S) To a solution of tert-butyl (crude) 1, 1-dimethylethylenesulfonamido) methyl) piperidine-1-carboxylate in MeOH (20 mL) was added NaOH (0.45 g, 11.32 mmol) in portions. The resulting mixture was warmed to 50 ℃ and stirred for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) at room temperature and acidified to pH 4 with citric acid. The resulting solution was extracted with EA (2X 200 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 60% aqueous ACN (plus 0.05% TFA) to give 4- [ ((r)) as a yellow solidS) - (3, 4-dichloro-2-fluoro-6-hydroxyphenyl) ([ ((ii) ((iii))R) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester (0.60 g, 68% of two steps in total): C₂₁H₃₁Cl₂FN₂O₄S [M + H]⁺Calculated lcms (esi): 497, 499 (3: 2), found 497, 499 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 6.89 (d, J = 1.8 Hz, 1H), 4.59 (d, J = 8.2 Hz, 1H), 4.27-3.92 (m, 2H), 2.80-2.51 (m, 2H), 2.09-1.98 (m, 2H), 1.54-1.46 (m, 3H), 1.45 (s, 9H), 1.20 (s,9H)。

step f:

at room temperature to 4- [ ()S) - (3, 4-dichloro-2-fluoro-6-hydroxyphenyl) ([ ((ii) ((iii))R) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]A solution of piperidine-1-carboxylic acid tert-butyl ester (crude) in DCM (10 mL) was added TFA (2 mL) dropwise. The reaction solution was stirred at room temperature for 1 hour. The resulting solution was taken up in saturated NaHCO ₃The aqueous solution was adjusted to pH 8 and extracted with EA (2X 80 mL). The combined organic layers were washed with brine (2X 50 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give crude (A) as a pale yellow oilR)-N-[(S) - (3, 4-dichloro-2-fluoro-6-hydroxyphenyl) (piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.40 g, 83%). The crude product was used without further purification in the subsequent step: c₁₆H₂₃Cl₂FN₂O₂S [M + H]⁺Lcms (esi) calculated value of (a): 397, 399 (3: 2), found 397, 399 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 6.76 (s, 1H), 4.28 (d, J = 7.6 Hz, 1H), 3.52-3.40 (m, 1H), 3.30-3.20 (m, 1H), 3.03-2.80 (m, 2H), 2.55-2.40 (m, 1H), 2.38-2.22 (m, 1H), 1.59-1.37 (m, 3H), 1.10 (s, 9H)。

example 19 intermediate 19 ((2)R) -1-methyl-5-oxopyrrolidine-2-carboxylic acid lithium)

Step a:

stirring (2) under nitrogen at 0 deg.CR) To a solution of ethyl-5-oxopyrrolidine-2-carboxylate (0.50 g, 3.18 mmol) in THF (4 mL) was added NaH (0.25 g, 6.36 mmol, 60% in mineral oil). The resulting mixture was stirred at 0 ℃ for 10 minutes. MeI (0.90 g, 6.36 mmol) was then added to the mixture. The resulting mixture was stirred at 0 ℃ for 1 hour under nitrogen atmosphere. The reaction was quenched with water (3 mL) at 0 ℃. The resulting mixture was diluted with DCM (30 mL) and water (30 mL), and the aqueous layer was extracted with DCM (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give (2) as a pale yellow oilR) -1-methyl-5-oxopyrrolidine-2-carboxylic acid ethyl ester (0.22 g, 40%): C₈H₁₃NO₃ [M + H]⁺Calculated lcms (esi): 172 measured value: 172;¹H NMR (400 MHz, CDCl₃) δ 4.26 (q, J = 8.6, 7.9 Hz, 2H), 4.18-4.08 (m, 1H), 2.89 (s, 3H), 2.58-2.29 (m, 3H), 2.16-2.05 (m, 1H), 1.44-1.30 (m, 3H)。

step b:

stirring at room temperature (2)R) (iii) Ethyl (1-methyl-5-oxopyrrolidine) -2-carboxylate (0.15 g, 0.95 mmol) in MeOH (2 mL) to which LiOH H was added₂O (48 mg, 1.15 mmol) in H₂Solution in O (2 mL). The reaction mixture is added inStirred at room temperature for 16 hours. The resulting solution was concentrated under reduced pressure to give (2) as an off-white solidR) Lithium 1-methyl-5-oxopyrrolidine-2-carboxylate (0.15 g, crude), which was used without further purification in the subsequent step C₆H₉NO₃ [M + H]⁺Calculated lcms (esi): 144, found 144.

EXAMPLE 20 intermediate 20 (1-bromo-5-chloro-4-cyclobutyl-2-methoxybenzene)

Step a:

to a stirred mixture of 4-chloro-3-iodophenol (3.00 g, 11.79 mmol) and K at room temperature₂CO₃(3.26 g, 23.59 mmol) in DMF (30 mL) CH was added dropwise₃I (2.51 g, 17.69 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EA (50 mL) and water (100 mL). The aqueous solution was extracted with EA (3X 50 mL). The combined organic layers were washed with brine (6X 30 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (20/1) to give 1-chloro-2-iodo-4-methylbenzene (2.90 g, 92%) as a colorless oil:¹H NMR (400 MHz, CD₃OD) δ 7.47-7.41 (m, 1H), 7.41-7.33 (m, 1H), 6.99-6.90 (m, 1H), 3.78 (s, 3H)。

step b:

to a stirred solution of 1-chloro-2-iodo-4-methoxybenzene (1.00 g, 3.73 mmol) in THF (5 mL) was added dropwise under a nitrogen atmosphere at-78 deg.CnBuLi (2.2 mL, 5.59 mmol, 2.5M in hexane). The solution was stirred at-78 ℃ for 30 minutes under nitrogen. Cyclobutanone (0.39 g, 5.59 mmol) was then added to the solution. The resulting solution was stirred at-78 ℃ for 1 hour under nitrogen atmosphere. Reacting with saturated NH₄Aqueous Cl (3 mL) was quenched. The resulting mixture was diluted with EA (30 mL) and water (30 mL), and the aqueous solution was then extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (3/1) to give 1- (2-chloro-5-methoxyphenyl) cyclobutan-1-ol (0.56 g, 71%) as a pale yellow oil:¹H NMR (400 MHz, CD₃OD) δ 7.28 (dd, J = 8.7, 1.5 Hz, 1H), 6.96 (d, J = 3.0 Hz, 1H), 6.83 (dd, J = 8.7, 2.2 Hz, 1H), 3.81 (s, 3H), 2.75-2.63 (m, 2H), 2.50-2.37 (m, 2H), 2.23-2.12 (m, 1H), 1.78-1.66 (m, 1H)。

step c:

to a stirred mixture of 1- (2-chloro-5-methoxyphenyl) cyclobutan-1-ol (0.56 g, 2.63 mmol) and Et at room temperature under a nitrogen atmosphere ₃SiH (0.61 mg, 5.27 mmol) in DCM (3 mL) was added BF₃·Et₂O (0.75 g, 5.27 mmol). The solution was stirred at room temperature under nitrogen for 1 hour. The reaction was quenched with water (5 mL) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (20/1) to give 1-chloro-2-cyclobutyl-4-methoxybenzene (0.49 g, 95%) as a colorless oil:¹H NMR (400 MHz, CD₃OD) δ 7.21 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 3.0 Hz, 1H), 6.74 (dd, J = 8.7, 3.0 Hz, 1H), 3.81 (s, 3H), 3.79-3.72 (m, 1H), 2.47-2.33 (m, 2H), 2.19-1.97 (m, 3H), 1.92-1.81 (m, 1H)。

step d:

to a stirred solution of 1-chloro-2-cyclobutyl-4-methoxybenzene (0.48 g, 2.44 mmol) in HOAc (5 mL) was added dropwise Br at room temperature₂ (0.43 g, 2.69 mmol). The solution was stirred at room temperature for 1 hour. The reaction was saturated with Na₂SO₃The aqueous solution (2 mL) was quenched and diluted with EA (30 mL) and water (30 mL). The aqueous solution was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (20/1) to give 1-bromo-5-chloro-4-cyclobutyl-2-methoxybenzene (0.60 g, 72%) as a colorless liquid:¹H NMR (400 MHz, CD₃OD) δ 7.48 (s, 1H), 6.98 (s, 1H), 3.92 (s, 3H), 3.83-3.71 (m, 1H), 2.51-2.34 (m, 2H), 2.24-2.02 (m, 3H), 1.94-1.80 (m, 1H)。

example 21 intermediate 21 (1-bromo-5-chloro-4-fluoro-2- (prop-2-en-1-yloxy) benzene)

Step a:

to a stirred solution of 4-chloro-3-fluorophenol (2.00 g, 13.65 mmol) in DCM (15 mL) was added Br at room temperature ₂ (2.62 g, 16.40 mmol). The resulting solution was stirred at room temperature for 1 hour. The reaction was incubated with saturated Na at room temperature₂SO₃Aqueous solution (30 mL) was quenched. The aqueous layer was extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 2-bromo-4-chloro-5-fluorophenol (3.40 g, crude) as a pale yellow oil, which was used in the next step without further purification:¹H NMR (400 MHz, CD₃OD) δ 7.58 (d, J = 7.9 Hz, 1H), 6.79 (d, J =10.5H z, 1H).

Step b:

to stirred 2-bromo-4-chloro-5-fluorophenol (3.40 g, 15.08 mmol) and K at room temperature₂CO₃ (4.17 g, 30.17 mmol) in DMF (30 mL) was added 3-bromoprop-1-ene (2.74 g, 22.65 mmol) dropwise. The resulting mixture was stirred at room temperature for 1 hour. The reaction was diluted with EA (50 mL) and water (50 mL). The aqueous solution was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (6X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (20/1) to give 1-bromo-5-chloro-4-fluoro-2- (prop-2-en-1-yloxy) benzene (2.40 g, 60%) as a colorless oil:¹H NMR (400 MHz, CD₃OD) δ 7.68 (d, J = 7.9 Hz, 1H), 7.05 (d, J = 11.0 Hz, 1H), 6.14-6.02 (m, 1H), 5.50 (d, J =17.2 Hz, 1H), 5.33 (d, J = 10.6 Hz, 1H), 4.65 (d, J = 4.3 Hz, 2H)。

EXAMPLE 22 intermediate 22 (8- [ A)Oxy (methyl) carbamoyl ]-3-azabicyclo [ 2 ]3.2.1]Octane-3-carboxylic acid tert-butyl ester

Step a:

stirring of 3-azabicyclo [ alpha ], [ alpha ] -amino acid at room temperature3.2.1]Octane-8-carboxylic acid methyl ester hydrochloride (0.50 g, 2.43 mmol) and Et₃Boc was added to a solution of N (0.98 g, 9.72 mmol) in DCM (6 mL)₂O (0.80 g, 3.65 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was diluted with EA (20 mL) and water (30 mL). The aqueous solution was extracted with EA (3X 20 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was evaporated under reduced pressure to give 3-tert-butyl 8-methyl 3-azabicyclo [ 2 ] as a yellow oil3.2.1]Octane-3, 8-dicarboxylate (0.65 g, crude), which was used in the next step without further purification: c₁₄H₂₃NO₄ [M + H - 15]⁺Calculated lcms (esi): 255, found 255;¹H NMR (400 MHz, CDCl₃) δ 3.90 (d, J = 60.4 Hz, 1H), 3.79-3.60 (m, 4H), 3.17 (d, J = 41.4 Hz, 1H), 2.97-2.77 (m, 1H), 2.69-2.41 (m, 3H), 1.85-1.61 (m, 4H), 1.47 (d, J = 3.7 Hz, 9H)。

step b:

to the stirred 3-tert-butyl 8-methyl 3-azabicyclo [ 2 ] at room temperature3.2.1]To a solution of octane-3, 8-dicarboxylate (0.65 g, 2.41 mmol) in MeOH (5 mL) was added a solution of NaOH (0.19 g, 4.83 mmol) in water (2 mL). The reaction was stirred at 40 ℃ for 1 hour. After cooling to room temperature, the resulting solution was diluted with EA (20 mL) and water (30 mL). The aqueous solution was acidified to pH 3 with citric acid and then extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was evaporated under reduced pressure to give 3- (tert-butoxycarbonyl) -3-azabicyclo [ 2 ] in the form of a yellow oil3.2.1]Octane-8-carboxylic acid (0.70 g, crude), which was used without further purificationThe next step is: c₁₃H₂₁NO₄ [M + H -56]⁺Lcms (esi) calculated value of (a): 200, found 200;¹H NMR (400 MHz, CD₃OD) δ 3.88 (d, J = 12.5 Hz, 1H), 3.68 (d, J = 13.1 Hz, 1H), 3.32-3.13 (m, 1H), 3.05-2.75 (m, 3H), 2.73-2.36 (m, 2H), 1.89-1.74 (m, 2H), 1.64-1.55 (m, 1H), 1.47 (s, 9H)。

step c:

to the stirred 3- (tert-butoxycarbonyl) -3-azabicyclo [ 2 ] at room temperature3.2.1]Octane-8-carboxylic acid (0.70 g, 2.74 mmol), HOBt (0.56 g, 4.11 mmol) and EDCI (0.79 g, 4.11 mmol) in DMF (6 mL) were addedN,ODimethylhydroxylamine hydrochloride (0.40 g, 4.11 mmol) and Et₃N (0.55 g, 5.48 mmol). The reaction was stirred at room temperature for 16 hours. The reaction was diluted with EA (30 mL) and water (30 mL). The aqueous solution was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (6X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with PE/EA (2/1) to give 8- [ methoxy (methyl) carbamoyl group as a pale yellow oil]-3-azabicyclo [ 2 ]3.2.1]Octane-3-carboxylic acid tert-butyl ester (0.43 g, 53%): C₁₅H₂₆N₂O₄ [M + H - 56]⁺Calculated lcms (esi): 243, measured value 243;¹H NMR (400 MHz, CDCl₃) δ 3.91 (d, J = 47.8 Hz, 1H), 3.73 (d, J = 10.9 Hz, 3H), 3.69-3.39 (m, 2H), 3.21 (d, J = 12.8 Hz, 3H), 3.03-2.84 (m, 1H), 2.74 (d, J = 17.2 Hz, 1H), 2.55-2.33 (m, 3H), 2.03-1.88 (m, 1H), 1.84-1.57 (m, 2H), 1.47 (d, J = 7.2 Hz, 9H)。

example 23 intermediate 23 (, (b)S)-N-[(R) - (4-bromo-5-chloro-2-methoxyphenyl) ([1- [ (4) R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide)

Step a:

stirred 3-bromo-4-chlorophenol (5.00 g, 24.10 mmol) and K at 40 deg.C₂CO₃(9.99 g, 72.31 mmol) in THF (50 mL) was added MeI (10.26 g, 72.31 mmol) dropwise. The reaction mixture was stirred at 40 ℃ for 16 hours. The resulting mixture was diluted with water (50 mL) and extracted with EA (3X 100 mL). The combined organic layers were washed with brine (2X 100 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE to give 2-bromo-1-chloro-4-methoxybenzene (4.50 g, 84%) as a colorless oil:¹H NMR (400 MHz, CD₃OD) δ 7.41 (d, J = 8.9 Hz, 1H), 7.26 (d, J = 2.9 Hz, 1H), 6.93 (dd, J = 8.9, 2.9 Hz, 1H), 3.81 (s, 3H)。

step b:

to a stirred solution of 2-bromo-1-chloro-4-methoxybenzene (2.00 g, 9.03 mmol) in DCM (20 mL) was added AgOTf (2.55 g, 9.93 mmol) at room temperature. After addition, I₂(2.52 g, 9.93 mmol) was added to the reaction and the mixture was stirred at room temperature for 3 hours. The reaction was quenched with saturated Na at room temperature₂SO₃Aqueous solution (50 mL) was quenched and extracted with EA (3X 60 mL). The combined organic layers were washed with brine (3X 50 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE to give 1-bromo-2-chloro-4-iodo-5-methoxybenzene (2.50 g, 80%) as an off-white solid: ¹H NMR (400 MHz, CDCl₃) δ 7.84 (s, 1H), 7.04 (s, 1H), 3.89 (s, 3H)。

Step c:

to a solution of 1-bromo-2-chloro-4-iodo-5-methoxybenzene (10.00 g, 28.79 mmol) in THF (20 mL) was added dropwise over 10 minutes at-90 deg.C under a nitrogen atmospherenBuLi (11.5 mL, 28.75 mmol, 2.5M in hexane). The solution was stirred at the same temperature for 30 minutes. At-90 deg.C 4- [ [ (C)S) -2-methylpropan-2-sulfinyl]Imino radical]Methyl radical]A solution of tert-butyl piperidine-1-carboxylate (9.10 g, 28.79 mmol) in THF (10 mL) was added quickly to the above solution (reaction temperature from-90 to-70 ℃ at room temperature. After addition, the reaction was stirred at-75 ℃ for an additional 1.5 hours. The reaction is passed through saturated NH₄Aqueous Cl (20 mL) was quenched and then diluted with water (100 mL). The aqueous phase was extracted with EA (3X 100 mL). The combined organic layers were washed with brine (2X 50 mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with a solution containing 10 mmol/L NH₄HCO₄Eluting with 60% ACN aqueous solution to obtain 4- [ (II) as off-white solidR) - (4-bromo-5-chloro-2-methoxyphenyl) ([ ((ii) ((iii))S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester (12.40 g, 80%) C₂₂H₃₄BrClN₂O₄S [M + H]⁺Calculated lcms (esi): 537, 539 (2: 3: 1), found 537, 539 (2: 3: 1); ¹H NMR (400 MHz, CD₃OD) δ 7.43 (s, 1H), 7.30 (s, 1H), 4.44 (d, J = 8.9 Hz, 1H), 4.16 (d, J =13.4 Hz, 1H), 4.01 (d, J = 13.1 Hz, 1H), 3.85 (s, 3H), 2.84-2.57 (m, 2H), 2.17-2.05 (m, 1H), 2.02-1.84 (m, 1H), 1.545 (s, 9H), 1.30-1.08 (m, 3H), 1.13 (s, 9H)。

Step d:

to stirred 4- [ (ii) ((iii)) at room temperatureR) - (4-bromo-5-chloro-2-methoxyphenyl) ([ ((ii) [))S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]A solution of piperidine-1-carboxylic acid tert-butyl ester (6.00 g, 11.19 mmol) in DCM (60 mL) was added TFA (10 mL) dropwise. The resulting mixture was stirred at room temperature for 30 minutes. The reaction was quenched with saturated NaHCO at room temperature₃Aqueous solution (50 mL) was neutralized. The aqueous layer was extracted with DCM (3X 200 mL). The combined organic layers were concentrated under reduced pressure to give (in the form of a yellow oil) ((S)-N-[(R) - (4-bromo-5-chloro-2-methoxyphenyl) (piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (4.60 g, crude). The crude product was used without further purification in the subsequent step: c₁₇H₂₆BrClN₂O₂S [M + H]⁺Calculated lcms (esi): 437, 439 (2: 3: 1), found 437, 439 (2: 3: 1);¹H NMR (400 MHz, CD₃OD) δ 7.45 (s, 1H), 7.35 (s, 1H), 4.50 (d, J = 9.1 Hz, 1H), 3.90 (s, 3H), 3.47 (d, J = 12.8 Hz, 1H), 3.30-3.25 (m, 1H), 3.01-2.80 (m, 2H), 2.42-2.33 (m, 1H), 2.19-2.06 (m, 1H), 1.57-1.28 (m, 3H), 1.14 (s, 9H)。

step e:

stirring at room temperature (4)R) (1.70 g, 11.63 mmol) of (E) -2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid and a solution of HATU (4.43 g, 11.65 mmol) in DMF (10 mL) was addedS)-N-[(R) - (4-bromo-5-chloro-2-methoxyphenyl) (piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (3.40 g, 7.76 mmol) and Et₃N (2.36 g, 23.29 mmol). The resulting solution was stirred at room temperature for 1 hour. The resulting solution was quenched with water (60 mL) and extracted with EA (3X 100 mL). The combined organic layers were washed with brine (2X 30 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography using a column containing 10 mmol/L NH₄HCO₃Is eluted as an off-white solid with 70% aqueous ACN solution (a), (b), (c) and c), (c) and c)S)-N-[(R) - (4-bromo-5-chloro-2-methoxyphenyl) ([1- [ (4)R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl]) Methyl radical]2-methylpropane-2-sulfinamide (3.80 g, 86%): C₂₃H₃₄BrClN₂O₅S [M + H]⁺Lcms (esi) calculated value of (a): 565, 567 (2: 3: 1), found 565, 567 (2: 3: 1);¹H NMR (400 MHz, CD₃OD) δ 7.43 (d, J =2.7 Hz, 1H), 7.31 (d, J = 1.8 Hz, 1H), 5.48-5.32 (dd, J = 33.5, 7.5 Hz, 1H), 4.59-4.37 (m, 2H), 4.20-4.10 (m, 1H), 4.32-4.18 (m, 2H), 3.88 (d, J = 2.2 Hz, 3H), 3.20-2.90 (m, 1H), 2.73-2.56 (m, 1H), 2.25-2.06 (m, 2H), 1.48-1.33 (m, 8H), 1.17-1.09 (m, 10H)。

example 24 intermediate 24 (, (b)S)-N-[(R) - [ 4-bromo-5-chloro-2- (prop-2-en-1-yloxy) phenyl]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide)

Step a:

to a stirred solution of 1-bromo-2-chloro-4-iodo-5-methoxybenzene (47.00 g, 135.30 mmol) in DCM (470 mL) was added BBr dropwise under nitrogen at 0 deg.C₃(101.00 g, 405.90 mmol). The reaction solution was stirred at room temperature for 20 hours under nitrogen atmosphere. The reaction was quenched with water (500 mL) and extracted with EA (3X 500 mL) at 0 ℃. The combined organic layers were washed with brine (3X 500 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 5-bromo-4-chloro-2-iodophenol (45.50 g, 95%) as a pale yellow solid, which was used in the subsequent steps without further purification.

Step b:

to a stirred solution of 5-bromo-4-chloro-2-iodophenol (45.20 g, 141.59 mmol) in DMF (100 mL) at room temperature under nitrogen was added dropwise K₂CO₃(39.14 g, 283.18 mmol) and allyl bromide (29.12 g, 240.70 mmol). The resulting mixture was stirred at room temperature under nitrogen for 1 hour. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EA (3X 200 mL). The combined organic layers were washed with brine (3X 100 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE to give 1-bromo-2-chloro-4-iodo-5- (prop-2-en-1-yloxy) benzene (28.50 g, 54%) as a colorless oil:¹H NMR (400 MHz, CDCl₃) δ 7.85 (d, J = 1.0 Hz, 1H), 7.02 (d, J = 0.9 Hz, 1H), 6.12-5.98 (m, 1H), 5.53 (dq, J = 17.2, 1.6 Hz, 1H), 5.37 (dq, J = 10.7, 1.4 Hz, 1H), 4.59 (dq, J = 4.6, 1.5 Hz, 2H)。

step c:

to a stirred solution of 1-bromo-2-chloro-4-iodo-5- (prop-2-en-1-yloxy) benzene (10.00 g, 26.78 mmol) in THF (250 mL) at-100 deg.C under a nitrogen atmosphere was added dropwisenBuLi (10.71 mL, 26.78 mmol, 2.5M in hexane). After stirring at-100 ℃ for 30 minutes under nitrogen atmosphere, 4- [ [ (C. (E) (C.))S) -2-methylpropan-2-sulfinyl]Imino radical]Methyl radical]A solution of tert-butyl piperidine-1-carboxylate (8.47 g, 26.7 mmol) in THF (40 mL) was added dropwise to the mixture at-100 deg.C. The resulting mixture was stirred at-100 ℃ for an additional 1 hour. The reaction was carried out at-100 ℃ with saturated NH ₄Aqueous Cl (200 mL) was quenched. The aqueous layer was extracted with EA (3X 200 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 70% aqueous ACN (plus 0.05% TFA) to give 4- [ ((r)) as a pale yellow oilR) - [ 4-bromo-5-chloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester (10.00 g, 60%): C₂₄H₃₆BrClN₂O₄S [M + H]⁺Calculated lcms (esi): 563, 565 (2: 3: 1), found 563, 565 (2: 3: 1); ¹H NMR (400 MHz, CDCl₃) δ 7.22 (s, 1H), 7.12 (s, 1H), 6.11-5.96 (m, 1H), 5.48-5.30 (m, 2H), 4.61-4.55 (m, 2H), 4.46 (s, 1H), 4.24-4.02 (m, 2H), 2.74-2.47 (m, 2H), 2.03-1.77 (m, 2H), 1.46 (s, 9H), 1.40-1.11 (m, 3H), 1.18 (s, 9H)。

step d:

4- [ (ii) to stirring at room temperatureR) - [ 4-bromo-5-chloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]A solution of tert-butyl piperidine-1-carboxylate (5.60 g, 9.96 mol) in DCM (50 mL) was added TFA (10 mL) dropwise. The reaction solution was stirred at room temperature for 0.5 hour. The reaction was quenched with saturated NaHCO at room temperature₃Neutralizing with water solution. The aqueous layer was extracted with EA (3X 100 mL). The combined organic layers were concentrated under reduced pressure to give (a) in the form of a pale yellow semisolidS)-N-[(R) - [ 4-bromo-5-chloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide (5.30 g, crude). The crude product was used without further purification in the subsequent step: c ₁₉H₂₈BrClN₂O₂S [M + H]⁺Lcms (esi) calculated value of (a): 463, 465 (2: 3: 1), found 463, 465 (2: 3: 1); ¹H NMR (400 MHz, CDCl₃) δ 7.25 (s, 1H), 7.13 (s, 1H), 6.08-5.98 (m, 1H), 5.46-5.34 (m, 2H), 4.62-4.51 (m, 2H), 4.45-4.36 (s, 1H), 4.25-4.18 (m, 1H), 3.49-3.34 (dd, J = 32.3, 12.9 Hz, 2H), 2.90-2.73 (m, 2H), 2.26-1.97 (m, 2H), 1.80-1.52 (m, 3H), 1.18 – 1.09 (s, 9H)。

step e:

stirred at room temperature (4)R) (2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid (2.50 g, 17.13 mmol) and HATU (6.52 g, 17.13 mmol) in DMF (30 mL) was addedS)-N-[(R) - [ 4-bromo-5-chloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide (5.30 g, 11.42 mmol) and Et₃N (3.47 g, 34.27 mmol). The reaction solution was stirred at room temperature for 1 hour. The resulting solution was quenched with water (60 mL) and extracted with EA (3X 100 mL). The combined organic layers were washed with brine (2X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with a solution containing 10 mmol/L NH₄HCO₃Is eluted in 70% aqueous ACN to give (a) as an off-white solidS)-N-[(R) - [ 4-bromo-5-chloro-2- (prop-2-en-1-yloxy) phenyl]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]2-methylpropane-2-sulfinamide (3.80 g, 54%): C₂₅H₃₆BrClN₂O₅S [M + H]⁺Calculated lcms (esi): 591, 593 (2: 3: 1), found 591, 593 (2: 3: 1); ¹H NMR (400 MHz, CDCl₃) δ 7.24 (d, J = 22.6 Hz, 1H), 7.12 (s, 1H), 6.07-5.97 (m, 1H), 5.46-5.30 (m, 2H), 4.68-4.58 (m, 2H), 4.60-4.50 (m, 3H), 4.49-4.33 (m, 1H), 4.21-4.01 (m, 2H), 3.92-3.88 (m, 1H) 3.09-2.82 (m, 1H), 2.56 (t, J = 12.7 Hz, 1H), 2.19-1.96 (m, 2H), 1.57-1.25 (m, 9H), 1.17 (d, J = 11.7 Hz, 9H)。

example 25 intermediate 25 (, (ii)S)-N-((R) - (2- (allyloxy) -5-chloro-4-methylphenyl) (piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide)

A, step a:

to a stirred solution of 2-bromo-5-methylphenol (42.00 g, 224.56 mmol) in 1,1,1,3,3, 3-hexafluoropropan-2-ol (500 mL) was added NCS (31.00 g, 235.78 mmol) in portions at room temperature under an air atmosphere. The reaction solution was warmed to 50 ℃ and stirred under an air atmosphere for 16 hours. After cooling to room temperature, the resulting solution was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (50/1) to give 2-bromo-4-chloro-5-methylphenol (47.00 g, 90%) as a pale yellow solid:¹H NMR (400 MHz, CDCl₃) δ 7.45 (s, 1H), 6.93 (d, J = 0.8 Hz, 1H), 2.32 (d, J = 0.7 Hz, 3H)。

step b:

to a stirred mixture of 2-bromo-4-chloro-5-methylphenol (31.00 g, 0.14 mol) and K at room temperature under an air atmosphere₂CO₃ (39.00 g, 0.28 mol) to a mixture in DMF (300 mL) was added allyl bromide (29.00 g, 0.24 mol) dropwise. The reaction mixture was stirred at 40 ℃ for 16 hours under an air atmosphere. After cooling to room temperature, the resulting mixture was diluted with water (300 mL) and extracted with EA (3X 150 mL). The combined organic layers were washed with brine (6X 100 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (100/1) to give 1-bromo-5-chloro-4-methyl-2- (prop-2-en-1-yloxy) benzene (24.50 g, 66%) as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 7.53 (s, 1H), 6.77 (s, 1H), 6.12-6.02 (m, 1H), 5.50 (d, J = 17.3 Hz, 1H), 5.34 (d, J = 10.4 Hz, 1H), 4.63-4.56 (m, 2H), 2.34 (s, 3H)。

Step c:

to a stirred solution of 1-bromo-5-chloro-4-methyl-2- (prop-2-en-1-yloxy) benzene (29.00 g, 0.12 mol) in THF (900 mL) was added dropwise under a nitrogen atmosphere at-90 deg.CnBuLi (48 mL, 0.12 mol, 2.5M in hexane). After stirring at-90 ℃ for 40 minutes under nitrogen atmosphere, 4- [ [ (C.) (E.)S) -2-methylpropan-2-sulfinyl]Imino radical]Methyl radical]A solution of piperidine-1-carboxylic acid tert-butyl ester (35.57 g, 0.12 mol) in THF (80 mL) under a nitrogen atmosphere at-90 deg.C for 20 minAdded dropwise to the stirred solution. The resulting mixture was stirred for an additional 1 hour at-90 ℃ under nitrogen. The reaction was quenched with saturated NH at-90 deg.C₄Aqueous Cl (100 mL) was quenched. The reaction solution was concentrated under reduced pressure to remove THF. The aqueous layer was extracted with EA (3X 600 mL). The combined organic layers were washed with brine (3X 200 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography, eluting with PE/EA (1/1), to obtain 4- [ ((R) ()) in the form of light yellow oilR) - [ 5-chloro-4-methyl-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester (25.40 g, 44%): C₂₅H₃₉ClN₂O₄S [M + H]⁺Calculated lcms (esi): 499, 501 (3: 1), found 499, 501 (3: 1); ¹H NMR (400 MHz, CDCl₃) δ 7.09 (s, 1H), 6.74 (s, 1H), 6.10-5.93 (m, 1H), 5.47-5.26 (m, 2H), 4.61-4.50 (m, 2H), 4.41-4.28 (m, 1H), 4.21-4.04 (m, 2H), 3.95-3.73 (m, 1H), 2.82-2.47 (m, 2H), 2.41 (s, 3H), 2.10-1.96 (m, 1H), 1.93-1.75 (m, 1H), 1.47 (s, 9H), 1.37-1.21 (m, 3H), 1.12 (s, 9H)。

Step d:

4- [ (ii) to stirring at room temperatureR) - [ 5-chloro-4-methyl-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]A solution of tert-butyl piperidine-1-carboxylate (48.00 g, 95.77 mmol) in DCM (380 mL) was added TFA (96 mL) dropwise. The resulting mixture was stirred at room temperature for an additional 1 hour. The mixture was washed with saturated NaHCO₃The aqueous solution was basified to pH 8. The resulting mixture was extracted with EA (3X 1L). The combined organic layers were washed with brine (3X 300 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to obtain (A) as a pale yellow oilS)-N-[(R) - [ 5-chloro-4-methyl-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (33.10 g, 88%): C₂₀H₃₁ClN₂O₂S [M + 1]⁺Calculated lcms (esi): 399, 401 (3: 1), measured value 399, 401 (3: 1);¹H NMR (400 MHz, CDCl₃) δ 7.10 (s, 1H), 6.75 (s, 1H), 6.08-5.93 (m, 1H), 5.44-5.21 (m, 2H), 4.60-4.47 (m, 2H), 4.34-4.22 (m, 2H), 3.43 (d, J = 13.0 Hz, 1H), 3.34 (d, J = 13.0 Hz, 1H), 2.88-2.72 (m, 2H), 2.34 (s, 3H), 2.12 (d, J =z, 2H) for 10.5 hours, 1.69-1.51 (m, 3H), 1.10 (s, 9H).

Example 26 intermediate 26: (N- [ (1-acetylpiperidin-4-yl) (4, 5-dichloro-2-methoxyphenyl) methylene]-2-methylpropane-2-sulfinamide)

Step a:

to a stirred 1- [4- [ (4, 5-dichloro-2-methoxyphenyl) carbonyl group at room temperature under a nitrogen atmosphere]Piperidin-1-yl radical]Ethan-1-one (0.30 g, 0.91 mmol) and Ti (OEt) ₄(0.41 g, 1.82 mmol) in THF (10 mL) was added 2-methylpropane-2-sulfinamide (0.22 g, 1.82 mmol). The resulting mixture was stirred at 70 ℃ for 16 hours under nitrogen atmosphere. After cooling to room temperature, the reaction was quenched with saturated NH₄Aqueous Cl (50 mL) was quenched and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (2X 50 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EA (2/1) to give a pale yellow oilN- [ (1-acetylpiperidin-4-yl) (4, 5-dichloro-2-methoxyphenyl) methylene]2-methylpropane-2-sulfinamide (0.27 g, 68%): C₁₉H₂₆Cl₂N₂O₃S[M + H]⁺Calculated lcms (esi): 433, 435 (3: 2), found 433, 435 (3: 2).

Example 27 intermediate 27 (, (b)2R,3S) -3- (benzoyloxy) oxolane-2-carboxylic acid)

Step a:

at 0 deg.C, in(4R,5S) To a solution of (E) -5- (hydroxymethyl) oxolane-2, 4-diol (15.00 g, 111.83 mmol) in MeOH (130 mL) was added H₂SO₄ (1.49 mL, 27.95 mmol, 97%) in MeOH (20 mL). The reaction was stirred at 0 ℃ to room temperature for 16 hours. The mixture was washed with saturated NaHCO₃The aqueous solution was neutralized to pH 7. The resulting mixture was filtered and the filter cake was washed with MeOH (3X 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (1/4) to give (A) 2S,3R) -2- (hydroxymethyl) -5-methoxyoxolan-3-ol (15.00 g, 91%):¹H NMR (400 MHz, DMSO-d ₆) δ 4.64 (t, J = 3.3 Hz, 1H), 4.52 (d, J = 5.5 Hz, 1H), 4.48-4.44 (m, 1H), 3.80-3.73 (m, 1H), 3.57-3.52 (m, 2H), 3.52-3.46 (m, 1H), 3.24-3.22 (m, 3H), 1.87-1.80 (m, 1H), 1.53 (dt, J = 12.8, 4.0 Hz, 1H)。

step b:

will be (A) and (B)2S,3R) A solution of (E) -2- (hydroxymethyl) -5-methoxyoxolane-3-ol (5.00 g, 33.75 mmol) and bis (trimethylsilyl) trifluoroacetamide (17.37 g, 67.48 mmol) in ACN (5 mL) was stirred at 80 ℃ for 5 h. After cooling to room temperature, Et was added at room temperature over 15 minutes₃SiH (19.62 g, 168.74 mmol) and TMSOTf (37.50 g, 168.72 mmol) were added portionwise to the above mixture. The resulting mixture was stirred at room temperature for another 16 hours. The reaction was quenched with water (30 mL) at 0 deg.C and saturated NaHCO₃The aqueous solution was neutralized to pH 7. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluted with EA to give (A) in the form of a pale yellow semisolid2S,3R) -2- (hydroxymethyl) oxolane-3-ol (1.40 g, 35%):¹H NMR (400 MHz, DMSO-d ₆) δ 4.93-4.77 (m, 1H), 4.71-4.54 (m, 1H), 3.82-3.67 (m, 2H), 3.57 (td, J = 5.3, 2.9 Hz, 1H), 3.40-3.33 (m, 1H), 1.98-1.85 (m, 1H), 1.74-1.63 (m, 1H)。

step c:

stirring at room temperature (2S,3R) (ii) -2- (hydroxymethyl) oxolane-3-ol (1.30 g, 11.01 mmol) and imidazole (0.76 g, 11.12 mmol) in DMF (8 mL) was added dropwiseTBDMSCl (1.66 g, 11.01 mmol) was added. The resulting solution was stirred at room temperature for 0.5 hour. The reaction was diluted with EA (50 mL) and water (50 mL). The aqueous solution was extracted with EA (2X 50 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was purified by column chromatography on silica gel, eluting with PE/EA (2/1), to give (in the form of a colorless oil) ((R))2S,3R) -2- [ [ (tert-butyldimethylsilyl) oxy ] group]Methyl radical]Oxetan-3-ol (1.54 g, 60%):¹H NMR (400 MHz, DMSO-d ₆) δ 4.88 (d, J = 4.2 Hz, 1H), 4.08-3.99 (m, 1H), 3.82-3.68 (m, 2H), 3.62-3.55 (m, 1H), 3.55-3.44 (m, 2H), 2.01-1.85 (m, 1H), 1.78-1.63 (m, 1H), 0.87 (s, 9H), 0.04 (d, J = 2.5 Hz, 6H)。

step d:

stirring at room temperature (2S,3R) -2- [ [ (tert-butyldimethylsilyl) oxy ] group]Methyl radical]To a solution of oxacyclopentane-3-ol (0.82 g, 3.53 mmol) and benzoic acid (0.56 g, 4.59 mmol) in THF (8 mL) was added Ph₃P (1.85 g, 7.05 mmol) and DEAD (1.23 g, 7.06 mmol). The resulting solution was stirred at room temperature for 1 hour. The reaction was diluted with EA (30 mL) and water (30 mL). The aqueous solution was extracted with EA (2X 30 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was purified by column chromatography on silica gel, eluting with PE/EA (6/1), to give (in the form of a colorless oil) ((R))2S,3S) -2- [ [ (tert-butyldimethylsilyl) oxy ] group]Methyl radical]Oxetane-3-benzoate (1.00 g, 84%):¹H NMR (400 MHz, CDCl₃) δ 8.06 (dt, J =8.2, 1.1 Hz, 2H), 7.66-7.55 (m, 1H), 7.47 (t, J = 7.7 Hz, 2H), 5.72-5.59 (m, 1H), 4.20-4.01 (m, 1H), 4.01-3.81 (m, 1H), 3.96 (td, J = 8.7, 4.8 Hz, 1H), 3.91 (dd, J = 6.3, 2.0 Hz, 2H), 2.48-2.32 (m, 1H), 2.20-2.08 (m, 1H), 0.85 (s, 9H), 0.05--0.05 (m, 6H)。

step e:

stirring at room temperature (2S,3S) -2- [ [ (tert-butyldimethylsilyl) oxy ] group]Methyl radical]Oxetane-3-benzoate (0.50 g, 1.49 mmol) in THF (3 m)L) and HOAc (0.1 mL) was added TBAF (2.97 mL, 2.970 mmol, 1M in THF). The reaction was stirred at room temperature for 3 hours. The reaction was diluted with EA (30 mL) and water (30 mL). The aqueous solution was extracted with EA (2X 30 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was purified by column chromatography on silica gel, eluting with PE/EA (1/4), to give (in the form of a colorless oil) ((R))2S,3S) -2- (hydroxymethyl) oxolane-3-benzoate (0.30 g, 91%):¹H NMR (400 MHz, DMSO-d ₆) δ 7.96-7.91 (m, 2H), 7.68-7.62 (m, 1H), 7.53 (t, J = 7.6 Hz, 2H), 5.51-5.46 (m, 1H), 3.97-3.86 (m, 2H), 3.81-3.72 (m, 1H), 3.65-3.57 (m, 2H), 2.40-2.29 (m, 1H), 2.02-1.93 (m, 1H)。

step f:

stirring at room temperature (2S,3S) To a solution of (2- (hydroxymethyl) oxolane-3-benzoate (0.34 g, 1.53 mmol) and (acetoxy) (phenyl) - λ 3-iodoalkyl acetate (0.74 g, 2.30 mmol) in ACN (3 mL) and water (3 mL) was added TEMPO (48 mg, 0.31 mmol). The reaction was stirred at room temperature for 16 hours. The resulting mixture was saturated with Na₂SO₃The aqueous solution (10 mL) was quenched and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (1/1) to give (b) (in the form of a colorless oil)2R,3S) -3- (benzoyloxy) oxolane-2-carboxylic acid (0.20 g, 55%):¹H NMR (400 MHz, DMSO-d ₆) δ 12.77 (s, 1H), 8.07-7.81 (m, 2H), 7.68 (t, J = 7.3 Hz, 1H), 7.56 (t, J = 7.3 Hz, 2H), 5.93-5.64 (m, 1H), 4.69-4.51 (m, 1H), 4.17-3.84 (m, 2H), 2.38-2.23 (m, 1H), 2.20-2.02 (m, 1H)。

EXAMPLE 28 intermediate 28 (lithium 4-methyl-5-oxomorpholine-2-carboxylate)

Step a:

to a stirred mixture of isoserine (50.00 g, 475.77 mmol) in MeOH (300 mL) at 0 deg.CIn-line adding SOCl₂(41. mL, 570.97 mmol). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure to give methyl 3-amino-2-hydroxypropionate (50.00 g, 71%) as an off-white solid ₄H₉NO₃ [M + H]⁺Lcms (esi) calculated value of (a): 120, measured value 120;¹H NMR (400 MHz, CD₃OD) δ 4.50 (dd, J =8.2, 4.0 Hz, 1H), 3.82 (s, 3H), 3.36-3.30 (m, 1H), (dd, J = 13.0, 8.3 Hz, 1H)。

step b:

to a stirred mixture of methyl 3-amino-2-hydroxypropionate (22.50 g, 188.89 mmol) and Et at room temperature₃A solution of N (57.34 g, 566.66 mmol) in DCM (300 mL) was added chloroacetyl chloride (21.33 g, 188.89 mmol) dropwise. The resulting mixture was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (1/2) to give methyl 3- (2-chloroacetylamino) -2-hydroxypropionate (13.00 g, 35%) as a yellow solid₆H₁₀ClNO₄ [M + H]⁺Calculated lcms (esi): 196, 198 (3: 1), found 196, 198 (3: 1);¹H NMR (400 MHz, CDCl₃) δ 6.97 (s, 1H), 4.35 (t, J = 5.0 Hz, 1H), 4.08 (s, 2H), 3.84 (s, 3H), 3.79-3.62 (m, 2H), 3.26 (s, 1H)。

step c:

to a stirred solution of methyl 3- (2-chloroacetamido) -2-hydroxypropionate (5.00 g, 25.56 mmol) in THF (300 mL) at room temperature under a nitrogen atmosphere was addedtBuOK (5.74 g, 51.15 mmol). The reaction was stirred at room temperature for 1 hour. After complete consumption of the starting material, MeI (4.35 g, 30.65 mmol) was added to the reaction. The mixture was stirred at room temperature for an additional 2 hours. The solution was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EA to give methyl 4-methyl-5-oxomorpholine-2-carboxylate (0.90 g, 20%) as a pale yellow semi-solid ₇H₁₁NO₄ [M + H]⁺Lcms (esi) calculated value of (a): 174, measured value 174;¹H NMR (400 MHz, CD₃OD) δ 4.61 (dd, J = 7.5, 4.8 Hz, 1H), 4.30 (d, J = 16.5 Hz, 1H), 4.19 (d, J = 16.6 Hz, 1H), 3.78 (s, 3H), 3.63 (dd, J = 6.2, 4.1 Hz, 2H), 2.98 (s, 3H)。

step d:

to a stirred solution of methyl 4-methyl-5-oxomorpholine-2-carboxylate (0.15 g, 0.87 mmol) in MeOH (3 mL) at room temperature was added LiOH H₂A solution of O (73 mg, 1.73 mmol) in water (1 mL). The reaction solution was stirred at 40 ℃ for 1 hour. The reaction was concentrated under reduced pressure to give lithium 4-methyl-5-oxomorpholine-2-carboxylate (0.14 g, crude) as an off-white solid, which was used in the next step without further purification: c₆H₉NO₄ [M + H]⁺Calculated lcms (esi): 160, found 160.

EXAMPLE 29 intermediate 29 (3- [ methoxy (methyl) carbamoyl)]-8-azabicyclo [ 2 ]3.2.1]Octane-8-carboxylic acid tert-butyl ester

Step a:

8-azabicyclo [ 2 ] stirred at room temperature3.2.1]Octane-3-carboxylic acid methyl ester (1.00 g, 5.91 mmol) and Et₃Boc was added to a solution of N (1.20 g, 11.86 mol) in DCM (10 mL)₂O (1.60 g, 7.33 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was diluted with EA (50 mL) and water (50 mL). The separated aqueous solution was extracted with EA (3X 20 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 8-tert-butyl 3-methyl 8-azabicyclo [ 2 ] as a pale yellow oil 3.2.1]Octane-3, 8-dicarboxylic acid ester (1.30 g, 99%) C₁₄H₂₃NO₄ [M + H -15]⁺Lcms (esi) calculated value of (a): 255, found 255.

Step b:

to stirred 8-tert-butyl 3-methyl 8-azabicyclo [ alpha ], [ alpha ] -amino acid at room temperature3.2.1]To a solution of octane-3, 8-dicarboxylate (1.30 g, 4.83 mol) in MeOH (5 mL) was added NaOH (0.39 g, 9.65 mol) in H₂O (0.5 mL). The reaction was stirred at room temperature for 16 hours. The reaction was diluted with EA (50 mL) and water (50 mL). The aqueous solution was extracted with EA (3X 20 mL). The combined aqueous layers were acidified to pH 3 with citric acid and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na₂SO₄Drying, filtering, and concentrating the filtrate under reduced pressure to obtain (8- [ (tert-butoxy) carbonyl) as a pale yellow oil]-8-azabicyclo [ 2 ]3.2.1]Octane-3-carboxylic acid) (1.20 g, 97%) C₁₃H₂₁NO₄ [M + Na]⁺Calculated lcms (esi): 278, found 278;¹H NMR (300 MHz, CDCl₃) δ 4.40-4.21 (m, 2H), 2.94-2.79 (m, 1H), 2.06-1.98 (m, 2H), 1.98-1.84 (m, 2H), 1.84-1.73 (m, 2H), 1.73-1.59 (m, 2H), 1.49 (s, 9H)。

step c:

to a stirred 8- [ (tert-butoxy) carbonyl group at room temperature]-8-azabicyclo [ 2 ]3.2.1]Octane-3-carboxylic acid (1.20 g, 4.70 mmol) and Et₃To a solution of N (0.95 g, 9.40 mmol) in DCM (10 mL) was added CDI (0.91g, 5.64 mmol) and N,OMethoxy (methyl) amine hydrochloride (0.69 g, 7.05 mmol). The reaction was stirred at room temperature for 3 hours. The reaction was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with PE/EA (1/1) to give 3- [ methoxy (methyl) carbamoyl group as a pale yellow oil ]-8-azabicyclo [ 2 ]3.2.1]Octane-8-carboxylic acid tert-butyl ester (1.10 g, 69% of the total of the three steps): C₁₅H₂₆N₂O₄ [M + H - 56]⁺Calculated lcms (esi): 243, measured value 243;¹H NMR (400 MHz, CDCl₃) δ 4.40-4.23 (m, 1H), 3.82-3.76 (m, 1H), 3.76-3.71 (m, 3H), 3.35-3.21 (m, 1H), 3.19 (d, J = 2.6 Hz, 3H), 2.18-1.93 (m, 4H), 1.81-1.56 (m, 4H), 1.56-1.44 (m, 9H)。

EXAMPLE 30 intermediate 30 (3- [ methoxy (methyl) carbamoyl ] azetidine-1-carboxylic acid tert-butyl ester)

Step a:

to a stirred 1- [ (tert-butoxy) carbonyl group at room temperature]A solution of azetidine-3-carboxylic acid (2.00 g, 9.94 mmol) and CDI (1.80 g, 10.9 mmol) in DCM (10 mL) was added Et₃N (1.20 g, 11.93 mmol) and N,OMethoxy (methyl) amine hydrochloride (0.90 g, 14.91 mmol). The reaction solution was stirred at room temperature for 1 hour. The resulting solution was diluted with water (30 mL) at room temperature and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with PE/EA (1/1) to give 3- [ methoxy (methyl) carbamoyl group as a pale yellow oil]Azetidine-1-carboxylic acid tert-butyl ester (2.10 g, 78%): C₁₁H₂₀N₂O₄ [M + H - 56]⁺Calculated lcms (esi): 189, found 189;¹H NMR (300 MHz, CD₃OD) δ 4.14-3.99 (m, 4H), 3.89-3.76 (m, 1H), 3.72 (s, 3H), 3.22 (s, 3H), 1.46 (s, 9H)。

EXAMPLE 31 intermediate 31 (4-fluoro-4- [ methoxy (methyl) carbamoyl ] piperidine-1-carboxylic acid tert-butyl ester)

Step a:

to a stirred 1- [ (tert-butoxy) carbonyl group at room temperature ]Et was added to a solution of (2.00 g, 8.09 mmol) of (4-fluoropiperidine-4-carboxylic acid and CDI (2.60 g, 16.18 mmol) in DCM (10 mL)₃N (2.50 g, 24.27 mmol) and N,OMethoxy (methyl) amine hydrochloride (1.00 g, 16.18 mmol). The reaction solution was stirred at room temperature for 16 hours. The resulting solution was diluted with water (30 mL) at room temperature and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with PE/EA (3/1) to give 4-fluoro-4- [ methoxy (methyl) carbamoyl group as a colorless oil]Piperidine-1-carboxylic acid tert-butyl ester (1.50 g, 57%): C₁₃H₂₃FN₂O₄ [M + H - 56]⁺Calculated lcms (esi): 235, found 235;¹H NMR (400 MHz, CDCl₃) δ 4.01 (d, J = 13.5 Hz, 2H), 3.75 (s, 3H), 3.26 (s, 3H), 3.21-3.01 (m, 1H), 2.06 (dd, J = 19.6, 10.9 Hz, 5H), 1.49 (s, 9H)。

example 32 intermediate 32 (lithium 5- ((tert-butoxycarbonyl) amino) -1,3, 4-oxadiazole-2-carboxylate)

Step a:

to stirred ethyl 5-amino-1, 3, 4-oxadiazole-2-carboxylate (0.10 g, 0.64 mmol) and Et at room temperature₃Boc was added to a solution of N (0.19 g, 1.91 mmol) in DMF (1 mL)₂O (0.17 g, 0.76 mmol). The resulting solution was stirred at room temperature for 12 hours. The reaction was concentrated under reduced pressure. The residue was purified by reverse phase chromatography using a column chromatography column having 10 mmoL/L NH₄HCO₃Eluted with 55% aqueous ACN to give 5- [ [ (tert-butoxy) carbonyl ] in the form of a pale yellow oil ]Amino group]-ethyl 1,3, 4-oxadiazole-2-carboxylate (0.10 g, 55%): C₁₀H₁₅N₃O₅ [M + H - 56]⁺Lcms (esi) calculated value of (a): 202, measured value 202;¹H NMR (400 MHz, DMSO-d ₆) δ 4.38 (q, J = 7.1 Hz, 2H), 1.46 (d, J = 3.1 Hz, 9H), 1.32 (t, J = 7.1 Hz, 3H)。

step b:

to the stirred 5- [ [ (tert-butoxy) carbonyl group]Amino group]To a solution of ethyl (0.16 g, 0.62 mmol) of (E) -1,3, 4-oxadiazole-2-carboxylate in MeOH (2 mL) was added LiOH H₂O (78 mg, 1.87 mmol) in MeOH (3 mL) in water was added LiOH. H at room temperature₂O (48 mg, 1.15 mmol) in H₂O (2 mL) solution. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to give lithium 5- ((tert-butoxycarbonyl) amino) -1,3, 4-oxadiazole-2-carboxylate (0.16 g, crude) as an off-white solid, which was used in the next step without further purificationThe method comprises the following steps: c₈H₁₁N₃O₅ [M + H]⁺Calculated lcms (esi): 230, measured value 230;¹H NMR (400 MHz, DMSO-d ₆) δ 8.53 (s, 1H), 2.50 (s, 9H)。

EXAMPLE 33 intermediate 33 (3-iodo-1- (triphenylmethyl) -1H-pyrazoles)

Step a:

stirring 3-iodo-1 at room temperatureH-pyrazole (0.50 g, 2.59 mmol) in DCM (5 mL) was added TrtCl (0.86 g, 3.09 mmol) and Et₃N (0.52 g, 5.16 mmol). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (12/1) to give 3-iodo-1- (triphenylmethyl) -1 as an off-white solid H-pyrazole (0.60 g, 48%):¹H NMR (400 MHz, CDCl₃) δ 7.19-7.10 (m, 15H), 6.42 (d, J = 2.5 Hz, 2H)。

EXAMPLE 34 intermediate 34 (4-iodo-1- (triphenylmethyl) -1)H-pyrazoles)

A, step a:

to stirred 4-iodo-1 at room temperatureH-pyrazole (0.50 g, 2.59 mmol) in DCM (5 mL) was added TrtCl (0.86 g, 3.09 mmol) and Et₃N (0.52 g, 5.16 mmol). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (10/1) to give 4-iodo-1- (triphenylmethyl) -1 as an off-white solidH-pyrazole (0.80 g, 64%):¹H NMR (400 MHz, DMSO-d ₆) δ 7.75 (s, 1H), 7.45 (s, 1H), 7.40-7.35 (m, 9H), 7.07-7.00 (m, 6H)。

example 35 intermediate 35 (, (b)S) -3-methoxy-2- (triphenyl) benzeneMethoxy) propionate lithium)

Step a:

stirring at room temperature (2)S) -ethylene oxide-2-carboxylic acid methyl ester (2.00 g, 19.59 mmol) in MeOH (15 mL) Mg (OSO) was added₂CF₃)₂(3.15 g, 9.80 mmol). The resulting mixture was stirred at 40 ℃ for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with DCM/MeOH (10/1) to give (2) as a pale yellow oilS) Methyl (1.50 g, 46%) 2-hydroxy-3-methoxypropionate C₅H₁₀O₄ [M + H]⁺Calculated lcms (esi): 135, found 135;¹H NMR (400 MHz, CDCl₃) δ 4.34 (t, J = 3.4 Hz, 1H), 3.83 (s, 3H), 3.75-3.65 (m, 2H), 3.41 (s, 3H), 2.65 (brs, 1H)。

step b:

stirring at room temperature (2)S) To a solution of methyl-2-hydroxy-3-methoxypropionate (0.70 g, 5.22 mmol) and DMAP (64 mg, 0.52 mmol) in pyridine (8 mL) was added TrtCl (1.60 g, 5.74 mmol). The resulting solution was warmed to 80 ℃ and stirred for 24 h. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (10/1) to give (2) as an off-white solidS) -methyl 3-methoxy-2- (triphenylmethoxy) propionate (0.80 g, 33%):¹H NMR (400 MHz, DMSO-d ₆) δ 7.45-7.19 (m, 15H), 4.16 (t, J = 5.2 Hz, 1H), 3.53 (dd, J = 10.6, 5.5 Hz, 1H), 3.32-3.27 (m, 1H), 3.23 (s, 3H), 3.21 (s, 3H)。

step c:

stirring at room temperature (2)S) Methyl (3-methoxy-2- (triphenylmethoxy) propionate) (0.80 g, 2.13 mmol) in MeOH (8 mL) was addedLiOH·H₂A solution of O (0.45 g, 10.63 mmol) in water (3 mL). The resulting mixture was stirred at room temperature for 2 hours. Concentrating the obtained mixture under reduced pressure to obtain (A)S) -lithium 3-methoxy-2- (trityloxy) propionate (0.80 g, crude), which was used in the next step without further purification: c₂₃H₂₂O₄ [M + Na]⁺Calculated lcms (esi): 385, measured value 385.

EXAMPLE 36 intermediate 36 (lithium 1-oxo-1, 2-dihydroisoquinoline-4-carboxylate)

Step a:

to stirred 1-oxo-2 at room temperatureHTo a solution of-isoquinoline-4-carboxylic acid methyl ester (0.20 g, 1.00 mmol) in MeOH (2 mL) was added LiOH H₂O (84 mg, 2.00 mmol) in water (3 mL). The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated under reduced pressure to give lithium 1-oxo-1, 2-dihydroisoquinoline-4-carboxylate (0.20 g, crude), which was used in the next step without further purification: c ₁₀H₇NO₃ [M - H]⁺Lcms (esi) calculated value of (a): 188, found 188.

EXAMPLE 37 intermediate 37 (lithium 5-cyano-6-oxo-1, 6-dihydropyridine-3-carboxylate)

Step a:

to stirred 5-ethynyl-6-oxo-1 at room temperatureHTo a solution of methyl-3-pyridinecarboxylate (0.18 g, 1.00 mmol) in MeOH (2 mL) was added LiOH. H₂O (84 mg, 2.00 mmol) in water (3 mL). The resulting mixture was stirred at 40 ℃ for 0.5 hour. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure to give lithium 5-cyano-6-oxo-1, 6-dihydropyridine-3-carboxylate (0.20 g, crude), which was used in the next step without further purification: c₇H₄N₂O₃ [M - H]⁺Calculated lcms (esi): 163, measured value 163.

Example 38 intermediate 38: (N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]-2,2, 2-trifluoroacetamide)

Step a:

4- [ (ii) to stirring at room temperatureR) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]To a solution of piperidine-1-carboxylic acid tert-butyl ester (0.50 g, 0.96 mmol) in 1, 4-dioxane (8 mL) was added aqueous HCl (4N2 mL). The reaction solution was stirred at room temperature for 20 minutes. The reaction solution was saturated with Na at room temperature₂CO₃The aqueous solution was adjusted to pH 8. The resulting mixture was extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to obtain 4- [ (R) ((R) ()) as a yellow oilR) -amino [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester (0.40 g, crude), which was used in the next step without further purification: c₂₀H₂₈Cl₂N₂O₃ [M + H]⁺Calculated lcms (esi): 415, 417 (3: 2), found 415, 417 (3: 2).

Step b:

4- [ (ii) with stirring at 0 deg.CR) -amino [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester (0.40 g, 0.96 mmol) and Et₃To a solution of N (0.29 g, 2.89 mmol) in DCM (5 mL) was added TFAA (0.24 g, 1.16 mmol). The reaction solution was stirred at 0 ℃ for 0.5 hour. The reaction mixture was diluted with DCM (50 mL) and water (30 mL). The aqueous solution was extracted with DCM (2X 20 mL). The combined organic layers were washed with brine (2X 20 mL) and Na₂SO₄And (5) drying. Filtering, concentrating the filtrate under reduced pressure to obtain 4- [ ((R)) in the form of yellow oilR) - [4, 5-bisChloro-2- (prop-2-en-1-yloxy) phenyl](2,2, 2-trifluoroacetamido) methyl]Tert-butyl piperidine-1-carboxylate (0.40 g, crude), which was used in the next step without further purification: c₂₂H₂₇Cl₂F₃N₂O₄ [M + Na]⁺Calculated lcms (esi): 533, 535 (3: 2), found 533, 535 (3: 2); ¹H NMR (400 MHz, CDCl₃) δ 7.25 (s, 1H), 7.02 (s, 1H), 6.12-5.98 (m, 1H), 5.48-5.39 (m, 2H), 4.77 (t, J = 9.7 Hz, 1H), 4.69-4.56 (m, 2H), 4.10 (d, J = 16.0 Hz, 2H), 2.75-2.48 (m, 2H), 2.08-1.97 (m, 1H), 1.78 (d, J = 13.3 Hz, 1H), 1.45 (s, 9H), 1.31-1.20 (m, 3H)。

Step c:

4- [ (ii) to stirring at room temperatureR) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](2,2, 2-trifluoroacetamido) methyl]To a solution of tert-butyl piperidine-1-carboxylate (0.40 g, 0.78 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with a solution containing 10 mmol/L NH₄HCO₃Eluted with 50% ACN in water to give a pale yellow solidN-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]-2,2, 2-trifluoroacetamide (0.30 g, 76% of three steps in total): C₁₇H₁₉Cl₂F₃N₂O₂ [M + H]⁺Calculated lcms (esi): 411, 413 (3: 2), found 411, 413 (3: 2).

EXAMPLE 39 intermediate 39 (lithium 2- (oxetan-3-yloxy) acetate)

Step a:

to a stirred mixture of NaH (12.65 g, 316.16 mmol, 60%) in THF (300 mL) was added oxetan-3-ol (19.52 g, 263.47 mmol) dropwise at 0 deg.C under a nitrogen atmosphere. The reaction solution was stirred at room temperature for 0.5 hours under a nitrogen atmosphere. Under nitrogenTo the above mixture was added dropwise ethyl 2-bromoacetate (44.00 g, 263.47 mmol) under an atmosphere at 0 ℃. The reaction mixture was stirred at room temperature for an additional 2 hours. The resulting mixture was quenched with water (200 mL) and extracted with EA (3X 200 mL). The combined organic layers were washed with brine (30X 100 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (5/1) to give ethyl 2- (oxetan-3-yloxy) acetate (25.00 g, 59%) as a colorless oil:¹H NMR (400 MHz, CDCl₃) δ 4.79-4.72 (m, 2H), 4.72-4.67 (m, 2H), 4.67-4.59 (m, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.05 (s, 2H), 1.28 (t, J = 7.1 Hz, 3H)。

step b:

to a stirred solution of ethyl 2- (oxetan-3-yloxy) acetate (1.00 g, 6.24 mmol) in THF (2 mL) and MeOH (2 mL) at 0 deg.C was added LiOH H₂O (0.29 g, 6.89 mmol). The reaction solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure to give lithium 2- (oxetan-3-yloxy) acetate (0.70 g, crude) as an off-white solid, which was used in the next step without further purification:¹H NMR (400 MHz, D₂O) δ 4.77-4.74 (m, 1H), 4.71-4.68 (m, 2H), 4.59-4.53 (m, 2H), 3.79 (s, 2H)。

example 40 intermediate 40 (, (b)R) -3-methoxy-2- (triphenylmethoxy) lithium propionate)

Step a:

stirring at room temperature (2)R) -ethylene oxide-2-carboxylic acid methyl ester (1.00 g, 9.80 mmol) in MeOH (10 mL) Mg (OSO) was added₂CF₃)₂(1.58 g, 4.90 mmol). The resulting mixture was stirred at 40 ℃ for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with DCM/MeOH (10/1) to give (2) as a pale yellow oilR) -methyl 2-hydroxy-3-methoxypropionate (0.90 g, 55)%): C₅H₁₀O₄ [M + H]⁺Calculated lcms (esi): 135, found 135; ¹H NMR (400 MHz, CDCl₃) δ 4.33 (t, J = 3.7 Hz, 1H), 3.83 (d, J = 1.5 Hz, 3H), 3.76-3.65 (m, 2H), 3.41 (d, J = 1.5 Hz, 3H), 2.91-2.39 (brs, 1H)。

Step b:

stirring at room temperature (2)R) To a solution of methyl-2-hydroxy-3-methoxypropionate (0.50 g, 3.73 mmol) and DMAP (46 mg, 0.37 mmol) in pyridine (4 mL) was added TrtCl (1.14 g, 4.10 mmol). The resulting solution was stirred at 80 ℃ for 24 hours. The resulting mixture was diluted with water (20 mL) and extracted with EA (3X 20 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (10/1) to give (2) as an off-white solidR) -methyl 3-methoxy-2- (triphenylmethoxy) propionate (0.60 g, 34%):¹H NMR (400 MHz, DMSO-d ₆) δ 7.49-7.09 (m, 15H), 4.16 (t, J = 5.2 Hz, 1H), 3.53 (dd, J = 10.6, 5.5 Hz, 1H), 3.32-3.27 (m, 1H), 3.23 (s, 3H), 3.21 (s, 3H)。

step c:

stirring at room temperature (2)R) To a solution of methyl (3-methoxy-2- (triphenylmethoxy) propionate (0.60 g, 1.59 mmol) in MeOH (6 mL) was added LiOH. H₂O (0.33 g, 7.97 mmol) in water (2 mL). The resulting mixture was stirred at room temperature for 2 hours. Concentrating the obtained mixture under reduced pressure to obtain (A)R) -lithium 3-methoxy-2- (trityloxy) propionate (0.80 g, crude), which was used in the next step without further purification: LCMS (ESI) calculated value for C₂₃H₂₂O₄ [M + Na]^-385, measured value 385.

EXAMPLE 41 intermediate 41 ((1)R,5S,6R) -6- [ methoxy (methyl) carbamoyl ]-3-azabicyclo [ 2 ]3.1.0]Hexane-3-carboxylic acid tert-butyl ester

A, step a:

stirring at room temperature (1)R,5S,6R) -3- [ (tert-butoxy) carbonyl]-3-azabicyclo [ 2 ]3.1.0]Hexane-6-carboxylic acid (0.50 g, 2.20 mmol), HOBt (0.45 g, 3.30 mmol) and EDCI (0.63 g, 3.30 mmol) in DMF (6 mL) were addedN,ODimethylhydroxylamine hydrochloride (0.40 g, 4.11 mmol) and Et₃N (0.45 g, 4.40 mmol). The reaction solution was stirred at room temperature for 2 hours. The reaction was diluted with EA (30 mL) and water (30 mL). The aqueous solution was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (6X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was evaporated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 70% aqueous ACN (plus 0.05% TFA) to give (1) as a pale yellow oilR,5S,6R) -6- [ methoxy (methyl) carbamoyl]-3-azabicyclo [ 2 ]3.1.0]Hexane-3-carboxylic acid tert-butyl ester (0.30 g, 45%): C₁₃H₂₂N₂O₄ [M + H - 56]⁺Calculated lcms (esi): 215, measured value 215;¹H NMR (400 MHz, CDCl₃) δ 3.76 (s, 3H), 3.72-3.64 (m, 1H), 3.59 (d, J = 11.2 Hz, 1H), 3.52-3.41 (m, 3H), 3.22 (s, 3H), 2.15-2.04 (m, 1H), 2.02-1.93 (m, 1H), 1.47 (s, 9H)。

EXAMPLE 42 intermediate 42 (4- [ methoxy (methyl) carbamoyl ] -2-methylpiperidine-1-carboxylic acid tert-butyl ester)

Step a:

to a stirred solution of 2-methylpyridine-4-carboxylic acid (2.00 g, 14.58 mmol) in MeOH (10 mL) at room temperature was added PtO₂ (0.40 g, 1.75 mmol) and HCl (6) N1 mL). The reaction was degassed three times under hydrogen and in H₂ (50 atm.) stirring was carried out at 30 ℃ for 16 hours. The reaction was filtered, the filtrate was concentrated under reduced pressure to give 2-methylpiperidine-4-carboxylic acid methylester in the form of a pale yellow oilEster (2.00 g, 96%) used in the next step without further purification: c₈H₁₅NO₂ [M + H]⁺Lcms (esi) calculated value of (a): 158, found 158;¹H NMR (400 MHz, CD₃OD)δ 3.51-3.43 (m, 1H), 3.37 (s, 3H), 3.31-3.24 (m, 1H), 3.12-3.02 (m, 1H), 2.77 (tt, J = 12.4, 3.8 Hz, 1H), 2.30-2.16 (m, 2H), 1.77 (qd, J = 13.8, 4.3 Hz, 1H), 1.63-1.49 (m, 1H), 1.37 (d, J = 6.5 Hz, 3H)。

step b:

to a stirred mixture of methyl 2-methylpiperidine-4-carboxylate (2.00 g, 12.72 mmol) and Et at room temperature₃Boc was added to a mixture of N (2.57 g, 25.40 mmol) in DCM (10 mL)₂O (4.16 g, 19.06 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was diluted with EA (50 mL) and water (50 mL). The aqueous solution was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 1-tert-butyl 4-methyl 2-methylpiperidine-1, 4-dicarboxylate (3.3 g, crude) as a pale yellow oil, which was used in the next step without further purification. C₁₃H₂₃NO₄ [M + H - 56]⁺Calculated lcms (esi): 202 measured value: 202;¹H NMR (400 MHz, CDCl₃)δ 4.28-4.09 (m, 1H), 3.91-3.76 (m, 1H), 3.72 (s, 3H), 3.11 (td, J = 13.1, 4.1 Hz, 1H), 2.76-2.51 (m, 1H), 2.10-1.86 (m, 3H), 1.85-1.69 (m, 1H), 1.47 (s, 9H), 1.09 (d, J = 6.5 Hz, 3H)。

step c:

to a stirred solution of 1-tert-butyl 4-methyl 2-methylpiperidine-1, 4-dicarboxylate (3.30 g, 12.82 mmol) in MeOH (10 mL) at room temperature was added a solution of NaOH (1.03 g, 25.75 mmol) in water (2 mL). The reaction solution was stirred at 40 ℃ for 1 hour. The reaction was diluted with water (50 mL). The aqueous solution was acidified to pH 3 with citric acid and then extracted with EA (3X 50 mL). The combined organic layers were washed with brine (2X 30 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purifying the residue by reverse phase chromatographyElution with 23% aqueous ACN (plus 0.05% TFA) afforded 1- [ (tert-butoxy) carbonyl as a pale yellow semisolid]2-methylpiperidine-4-carboxylic acid (2.20 g, 71%): C₁₂H₂₁NO₄ [M + H -56]⁺Calculated lcms (esi): 188, found 188.

Step d:

to a stirred 1- [ (tert-butoxy) carbonyl group at room temperature]To a solution of (E) -2-methylpiperidine-4-carboxylic acid (1.80 g, 7.40 mmol), HOBt (1.50 g, 11.10 mmol) and EDCI (1.80 g, 11.10 mmol) in DCM (10 mL) was addedN,ODimethylhydroxylamine hydrochloride (1.08 g, 11.10 mmol) and Et₃N (1.50 g, 14.80 mmol). The reaction solution was stirred at room temperature for 1 hour. The reaction was diluted with water (50 mL). The aqueous solution was extracted with EA (3X 50 mL). The combined organic layers were washed with brine (2X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with PE/EA (4/1) to give 4- [ methoxy (methyl) carbamoyl group as a pale yellow oil]-2-methylpiperidine-1-carboxylic acid tert-butyl ester (1.50 g, 71%): C₁₄H₂₆N₂O₄ [M + H]⁺Calculated lcms (esi): 287, found: 287;¹H NMR (400 MHz, CDCl₃) δ 4.04-3.92 (m, 1H), 3.89-3.81 (m, 1H), 3.71 (s, 3H), 3.21 (s, 3H), 3.20-3.10 (m, 1H), 2.88 (d, J = 10.4 Hz, 1H), 2.01-1.90 (m, 1H), 1.90-1.76 (m, 2H), 1.73-1.60 (m, 1H), 1.49 (s, 9H), 1.19 (d, J = 6.4 Hz, 3H)。

example 43 intermediate 43a (4- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl ] -2-methylpiperidine-1-carboxylic acid tert-butyl ester containing the cis isomer, racemate); intermediate 43b (4- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl ] -2-methylpiperidine-1-carboxylic acid tert-butyl ester containing the trans isomer, racemate)

A, step a:

under nitrogen atmosphere at 0 deg.CNext, to a stirred solution of 1-bromo-4, 5-dichloro-2- (prop-2-en-1-yloxy) benzene (2.76 g, 9.78 mmol) in THF (10 mL) was added dropwisei-PrMgCl (4.86 mL, 9.72 mmol, 2M in THF). The reaction was stirred at 0 ℃ for 30 minutes. Then 4- [ methoxy (methyl) carbamoyl group]Tert-butyl-2-methylpiperidine-1-carboxylate (1.40 g, 4.89 mmol) was added to the reaction. The reaction mixture was stirred at 0 ℃ for 1 hour under nitrogen atmosphere. The resulting mixture was washed with saturated NH₄Aqueous Cl (5 mL) was quenched and diluted with water (30 mL). The aqueous solution was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with PE/EA (4/1) to give 4- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl in the form of pale yellow semisolid]-2-methylpiperidine-1-carboxylic acid tert-butyl ester (0.50 g, 24%): C₂₁H₂₇Cl₂NO₄ [M + H -56]⁺Calculated lcms (esi): 372, 374 (3: 2), measured 372, 374 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, J = 10.3 Hz, 1H), 7.07 (s, 1H), 6.17-5.98 (m, 1H), 5.56-5.28 (m, 2H), 4.69-4.59 (m, 2H), 4.23-4.02 (m, 1H), 3.93-3.78 (m, 1H), 3.56-3.39 (m, 1H), 3.17-3.02 (m, 1H), 2.06-1.81 (m, 1H), 1.81-1.57 (m, 2H), 1.57-1.43 (m, 10H), 1.09 (d, J =6.6 Hz, 3H). And tert-butyl 4- (4, 5-dichloro-2-hydroxybenzoyl) -2-methylpiperidine-1-carboxylate (1.00 g, 53%) as a pale yellow oil C ₁₈H₂₃Cl₂NO₄ [M + H - 56]⁺Lcms (esi) calculated value of (a): 332, 334 (3: 2), found 332, 334 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 12.30 (s, 1H), 7.79 (s, 1H), 7.17 (s, 1H), 4.21-4.02 (m, 1H), 3.96 (dd, J = 14.0, 6.9 Hz, 1H), 3.50-3.37 (m, 1H), 3.25-3.06 (m, 1H), 2.08-1.96 (m, 2H), 1.96-1.81 (m, 1H), 1.81-1.67 (m, 1H), 1.53 (s, 9H), 1.20 (d, J = 6.4 Hz, 3H)。

to a stirred mixture of tert-butyl 4- (4, 5-dichloro-2-hydroxybenzoyl) -2-methylpiperidine-1-carboxylate (1.00 g, 2.56 mmol) and K at room temperature₂CO₃ (0.71 g, 5.15 mmol) to a mixture in DMF (5 mL) was added 3-bromoprop-1-ene (0.47 g, 3.86 mmol). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with EA (30 mL) and water (30 mL), and the aqueous solution was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with PE/EA (10/1) to give 4- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl group as a pale yellow oil]-2-methylpiperidine-1-carboxylic acid tert-butyl ester (1.00 g, 90%). 4- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl]The total amount of tert-butyl (2-methylpiperidine-1-carboxylate) is 1.50 g (72%).

Step b:

4- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl]-2-methylpiperidine-1-carboxylic acid tert-butyl ester (1.50 g, 3.51 mmol) was isolated under SFC using the following conditions: column: CHIRALPAK IF, 2X 25 cm, 5 μm; mobile phase A: CO 2 ₂75%, mobile phase B: 25 percent of MeOH; flow rate: 40 mL/min; a detector: UV of 220/254 nm; retention time: RT (reverse transcription)₁3.29 minutes; RT (reverse transcription)₂3.85 minutes.

The 1 st peak was obtained at 3.29 minutes, from which the 4- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl group containing the two cis enantiomers was isolated as a pale yellow semi-solid]-2-methylpiperidine-1-carboxylic acid tert-butyl ester (0.50 g, 45%): C₂₁H₂₇Cl₂NO₄ [M + H -56]⁺Calculated lcms (esi): 372, 374 (3: 2), measured 372, 374 (3: 2); the 2 nd peak was obtained at 3.85 minutes, from which the 4- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl group containing the two trans enantiomers was isolated as a pale yellow semi-solid]-2-methylpiperidine-1-carboxylic acid tert-butyl ester (0.40 g, 36%): C₂₁H₂₇Cl₂NO₄ [M + H -56]⁺Calculated lcms (esi): 372, 374 (3: 2), measured 372, 374 (3: 2).

EXAMPLE 44 intermediate 44 ((2, 3-dichloro-6-methoxyphenyl) (piperidin-4-yl) methanol trifluoroacetic acid)

Step a:

to a stirred solution of 3, 4-dichlorophenol (100.00 g, 613.49 mmol) in DCM (1000 mL) was added Br dropwise under a nitrogen atmosphere at 0 deg.C₂(98.04 g, 613.49 mmol). The reaction solution was stirred at room temperature under nitrogen atmosphere for 16 hours. At 0 deg.C, the reaction was saturated with Na ₂S₂O₃Aqueous solution (500 mL) was quenched. The resulting mixture was extracted with EA (6X 400 mL). The combined organic layers were washed with brine (2X 400 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give a mixture (100 g, crude) of 2-bromo-4, 5-dichlorophenol and 2-bromo-3, 4-dichlorophenol as a yellow oil. The crude product was used directly in the next step without further purification.

Step b:

reaction of 2-bromo-4, 5-dichlorophenol and 2-bromo-3, 4-dichlorophenol (32 g, 125.04 mmol, 1 eq.) with K at 0 deg.C₂CO₃ (54.9 g, 396.87 mmol, 3 equiv.) to the crude mixture in MeCN (210 mL) MeI (16.5 mL, 116.05 mmol, 2 equiv.) was added dropwise. The reaction mixture was stirred at 50 ℃ for 4 hours. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with PE to give 2-bromo-3, 4-dichloro-1-methoxybenzene (8.7 g, 25.7%) as a white solid:¹H NMR (300 MHz, CDCl₃) δ 7.40 (dd, J = 9.0, 1.1 Hz, 1H), 6.79 (d, J= 8.9 Hz, 1H), 3.92 (s, 3H), and 1-bromo-4, 5-dichloro-2-methoxybenzene obtained as a white solid (24.3 g, 71.77%):¹H NMR (300 MHz, CDCl₃) δ 7.64 (s, 1H), 6.99 (s, 1H), 3.91 (s, 3H)。

step c:

to a solution of 2-bromo-3, 4-dichloro-1-methoxybenzene (0.80 g, 3.13 mmol) in THF (8 mL) was added dropwise under a nitrogen atmosphere at 0 deg.Ci-PrMgCl (2.0 mL, 19.76 mmol, 2M in THF). The reaction solution was stirred at 0 ℃ for 0.5 hour. Then 4-formyl is added dropwise at 0 ℃ under nitrogen atmosphere A solution of tert-butyl phenylpiperidine-1-carboxylate (0.67 g, 3.13 mmol) in THF (2 mL). After stirring at 0 ℃ for an additional 0.5 h, the reaction mixture was allowed to warm to room temperature and stirred under nitrogen for an additional 0.5 h. Saturated NH is used for reaction₄Aqueous Cl (40 mL) was quenched and extracted with EA (2X 40 mL). Combining the organic layers, passing over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with PE/EA (3/2) to give 4- [ (2, 3-dichloro-6-methoxyphenyl) (hydroxy) methyl) as an off-white foam]Piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 82%): C₁₈H₂₅Cl₂NO₄ [M + Na]⁺Calculated lcms (esi): 412, 414 (3: 2), found 412, 414 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.38 (d, J = 8.9 Hz, 1H), 6.83 (d, J = 8.9 Hz, 1H), 4.98 (d, J = 8.9 Hz, 1H), 4.21 (d, J = 13.5 Hz, 1H), 4.07 (d, J = 13.5 Hz, 1H), 3.92 (s, 3H), 2.70 (td, J =12.9, 2.8 Hz, 1H), 2.59 (td, J = 12.8, 3.0 Hz, 1H), 2.17-1.97 (m, 2H), 1.48 (s, 9H), 1.42-1.24 (m, 3H)。

step d:

to 4- [ (2, 3-dichloro-6-methoxyphenyl) (hydroxy) methyl group at room temperature]To a solution of tert-butyl piperidine-1-carboxylate (0.50 g, 1.28 mmol) in DCM (5 mL) was added TFA (2 mL). The reaction solution was stirred at room temperature for 1 hour and concentrated to give (2, 3-dichloro-6-methoxyphenyl) (piperidin-4-yl) methanolic trifluoroacetic acid (0.60 g, crude): C as a colorless oil₁₃H₁₇Cl₂NO₂ [M + H]⁺Calculated lcms (esi): 290, 292 (3: 2), found 290, 292 (3: 2).

Example 45 intermediate 45 (, (iii)S)-N-((R) - (2- (allyloxy) -4-chloro-5-methylphenyl) (piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide)

Step a:

to a stirred solution of 3-chloro-4-methylphenol (0.50 g, 3.51 mmol) in HOAc (5 mL) under nitrogen at room temperature was added dropwise Br₂(0.56 g, 3.51 mmol). The reaction solution was stirred at room temperature for 3 hours. The reaction solution was saturated with Na₂SO₃Aqueous solution (50 mL) was quenched and extracted with EA (2X 30 mL). The combined organic layers were washed with saturated NaHCO₃Washed with aqueous solution (2X 30 mL) over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was column chromatographed on silica gel, eluting with PE/EA (5/1), to give 2-bromo-5-chloro-4-methylphenol (0.70 g, 90%) as an off-white solid:¹H NMR (400 MHz, CDCl₃) δ 7.33 (s, 1H), 7.06 (s, 1H), 5.46 (s, 1H), 2.30 (s, 3H)。

step b:

to stirred 2-bromo-5-chloro-4-methylphenol (0.70 g, 3.16 mmol) and K at room temperature₂CO₃(0.87 g, 6.32 mmol) to a mixture in DMF (5 mL) was added 3-bromoprop-1-ene (0.50 g, 4.11 mmol). The reaction mixture was warmed to 40 ℃ and stirred for 3 hours. The reaction mixture was diluted with water (50 mL) and extracted with EA (2X 15 mL). The combined organic layers were washed with brine (3X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE to give 1-bromo-4-chloro-5-methyl-2- (prop-2-en-1-yloxy) benzene as an off white solid (0.45 g, 54%): ¹H NMR (400 MHz, CDCl₃) δ 7.42 (s, 1H), 6.90 (s, 1H), 6.12-6.02 (m, 1H), 5.58-5.40 (m, 1H), 5.40-5.30 (m, 1H), 4.59 (dt, J =5.0, 1.6 Hz, 2H), 2.30 (s, 3H)。

Step c:

to a stirred solution of 1-bromo-4-chloro-5-methyl-2- (prop-2-en-1-yloxy) benzene (0.43 g, 1.64 mmol) in THF (4 mL) at-65 deg.C under a nitrogen atmosphere was added dropwisenBuLi (0.76 mL, 1.90 mmol, 2.5M in hexane). After stirring for 30 minutes, 4- [ [ (C) was added dropwise at-65 ℃ under a nitrogen atmosphereS) -2-methylpropan-2-sulfinyl]Imino radical]Methyl radical]A solution of tert-butyl piperidine-1-carboxylate (0.40 g, 1.26 mmol) in THF (2 mL). The resulting mixture was allowed to warm to room temperature, andthe mixture was stirred for 1 hour. Reacting with saturated NH₄Aqueous Cl (30 mL) was quenched. The resulting mixture was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography, eluting with PE/EA (1/5), and obtaining 4- (R) in the form of light yellow oilR) - (2- (allyloxy) -4-chloro-5-methylphenyl) (((s))S) Tert-butylsulfinyl) amino) methyl) piperidine-1-carboxylic acid tert-butyl ester (0.18 g, 30%) C₂₅H₃₉ClN₂O₄S [M + H]⁺Calculated lcms (esi): 499, 501 (3: 1), found 499, 501 (3: 1);¹H NMR (400 MHz, CDCl₃) δ 6.96 (s, 1H), 6.87 (s, 1H), 6.09-5.99 (m, 1H), 5.50-5.27 (m, 2H), 4.61-4.45 (m, 2H), 4.42-3.82 (m, 4H), 2.66-2.57 (m, 2H), 2.29 (s, 3H), 1.92-1.91 (m, 1H), 1.66 (s, 3H), 1.45 (s, 9H), 1.13 (s, 9H)。

step d:

4- (C) to stirring at room temperatureR) - (2- (allyloxy) -4-chloro-5-methylphenyl) (((s))S) -tert-butylsulfinyl) amino) methyl) piperidine-1-carboxylic acid tert-butyl ester (0.18 g, 0.38 mmol) in DCM (4 mL) was added TFA (1 mL). The reaction solution was stirred at room temperature for 1 hour. The resulting solution was taken up with saturated NaHCO at room temperature ₃Aqueous solution (20 mL) was quenched and extracted with DCM (3X 20 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to obtain (A) as a pale yellow oilS)-N-((R) - (2- (allyloxy) -4-chloro-5-methylphenyl) (piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (0.10 g, 70%): C₂₀H₃₁ClN₂O₂S [M + H]⁺Lcms (esi) calculated value of (a): 399, 401 (3: 1), found 399, 401 (3: 1).

EXAMPLE 46 intermediate 46 (1-bromo-4, 5-dichloro-3-fluoro-2- (prop-2-en-1-yloxy) benzene)

Step a:

to a solution of 3-chloro-2-fluorophenol (1.50 g, 10.23 mmol) in MeCN (60 mL) and TFA (1.00 mL) was added NCS (1.37 g, 10.24 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (5/1) to give 3, 4-dichloro-2-fluorophenol (1.60 g, 86%) as an off-white solid:¹H NMR (400 MHz, DMSO-d ₆) δ 10.64 (s, 1H), 7.27 (dd, J = 9.0, 2.1 Hz, 1H), 6.97 (t, J = 8.9 Hz, 1H)。

step b:

to a stirred solution of 3, 4-dichloro-2-fluorophenol (1.60 g, 8.84 mmol) in AcOH (20 mL) was added Br dropwise at room temperature₂(1.55 g, 9.72 mmol). The reaction solution was stirred at room temperature for 3 hours. The reaction mixture was poured into water (100 mL). The reaction mixture was then extracted with EA (2X 50 mL). The organic phase was saturated with Na ₂SO₃Aqueous solution (2X 50 mL), saturated NaHCO₃Aqueous (2X 50 mL) and brine (2X 50 mL). Then the solution is passed over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was column chromatographed on silica gel, eluting with PE/EA (5/1), to give 6-bromo-3, 4-dichloro-2-fluorophenol (1.80 g, 78%) as an off-white solid:¹H NMR (400 MHz, CDCl₃) δ 7.45 (d, J = 2.3 Hz, 1H)。

step c:

to stirred 6-bromo-3, 4-dichloro-2-fluorophenol (1.80 g, 6.97 mmol) and K at room temperature₂CO₃(2.00 g, 14.47 mmol) to a mixture in DMF (20 mL) was added 3-bromoprop-1-ene (1.26 g, 10.39 mmol). The reaction was then stirred at 40 ℃ for 3 hours. The reaction mixture was diluted with water (80 mL) and extracted with EA (2X 50 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE to give 1-bromo-4, 5-dichloro-3-fluoro-2- (prop-2-en-1-yloxy) benzene (1.70) as a colorless liquidg, 82%): ¹H NMR (400 MHz, CDCl₃) δ 7.50 (d, J =2.3 Hz, 1H), 6.18-6.03 (m, 1H), 5.47-5.37 (m, 1H), 5.32 (dd, J = 10.2, 1.5 Hz, 1H), 4.70-4.60 (m, 2H)； ¹⁹F NMR (376 MHz, CDCl₃) δ -121.32.

Example 47 intermediate 47 (, (b)R) -2-methoxy-3- (triphenylmethoxy) lithium propionate)

Step a:

stirring at room temperature (2)R) To a solution of methyl (2, 3-dihydroxypropionate) (0.50 g, 4.16 mmol) and (chlorodiphenylmethyl) benzene (3.50 g, 12.5 mmol) in DCM (4 mL) was added DMAP (30 mg, 0.25 mmol) and Et in portions ₃N (1.26 g, 12.5 mmol). The resulting mixture was stirred at room temperature under nitrogen for 72 hours. The resulting mixture was diluted with water (20 mL) and extracted with EA (3X 25 mL). The combined organic layers were washed with brine (3X 5 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (8/1) to give (2) as an off-white solidR) -methyl 2-methoxy-3- (triphenylmethoxy) propionate (0.10 g, 6%).¹H NMR (400 MHz, CDCl₃) δ 7.37-7.29 (m, 15H), 4.31 (t, J = 3.5 Hz, 1H), 3.91 (dd, J = 14.0, 3.6 Hz, 2H), 3.87 (s, 3H)。

Step b:

stirring at room temperature (2)R) Methyl-2-hydroxy-3- (triphenylmethoxy) propionate (0.50 g, 1.38 mmol) and CH₃I (1 mL) in Et₂To a solution in O (5 mL) Ag was added in portions₂O (0.96 g, 4.14 mmol). The resulting mixture was stirred at room temperature under nitrogen for 16 hours. The resulting mixture was diluted with water (20 mL) and extracted with DCM (3X 20 mL). The combined organic layers were washed with brine (3X 5 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EA (6/1) as an off-white solidFormula (2) toR) Methyl (2-methoxy-3- (triphenylmethoxy) propionate (0.40 g, 77%): C₂₄H₂₄O₄ [M + Na]⁺Calculated lcms (esi): 399, measured value 399; ¹H NMR (400 MHz, CDCl₃) δ 7.39-7.21 (m, 15H), 4.00-3.90 (m, 2H), 3.82 (s, 3H), 3.87-3.76 (m, 1H), 3.53 (s, 3H)。

Step c:

stirring at room temperature (2)R) To a mixture of methyl (50 mg, 0.13 mmol) 2-methoxy-3- (triphenylmethoxy) propionate in MeOH (2 mL) was added LiOH H₂O (9 mg, 0.4 mmol) in H₂Solution in O (1 mL). The resulting mixture was stirred at room temperature for 16 hours, and concentrated under reduced pressure to give (2)R) Lithium (50 mg, crude) 2-methoxy-3- (triphenylmethoxy) propionate. The crude product was used without further purification in the subsequent step: c₂₃H₂₂O₄ [M + Na]⁺Calculated lcms (esi): 385, measured value 385.

EXAMPLE 48 intermediate 48 ((2)S) -lithium 2-methoxy-3- (triphenylmethoxy) propionate)

Step a:

stirring at room temperature (2)S) To a solution of methyl (1.00 g, 8.32 mmol) 2, 3-dihydroxypropionate and (chlorodiphenylmethyl) benzene (2.50 g, 9.16 mmol) in DCM (10 mL) was added Et₃N (1.26 g, 12.5 mmol) and DMAP (61 mg, 0.50 mmol). The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with water (15 mL) and extracted with DCM (3X 20 mL). The combined organic layers were washed with brine (3X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EA (5/1) as an off white solid to give (2) S) -methyl 2-hydroxy-3- (triphenylmethoxy) propionate (1.00 g, 33%):¹H NMR (400 MHz, CDCl₃) δ 7.49-7.39 (m, 5H), 7.33 (dt, J = 6.9, 1.5 Hz, 5H), 7.33-7.22 (m, 5H), 4.32-4.27 (m, 1H), 3.80 (s, 3H), 3.54-3.45 (m, 1H), 3.38 (dd, J =9.4, 3.4 Hz, 1H)。

step b:

stirring at room temperature under air atmosphere (2)S) Methyl-2-hydroxy-3- (triphenylmethoxy) propionate (0.50 g, 1.38 mmol) and CH₃I (1 mL) in Et₂To a solution in O (5 mL) Ag was added in portions₂O (0.96 g, 4.14 mmol). The resulting mixture was stirred at room temperature under nitrogen for 16 hours. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with DCM (3X 20 mL). The combined organic layers were washed with brine (3X 25 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (6/1) to give (2) as an off-white solidS) Methyl (2-methoxy-3- (triphenylmethoxy) propionate (0.40 g, 77%): C₂₄H₂₄O₄[M + Na]⁺Calculated lcms (esi): 399, measured value 399;¹H NMR (400 MHz, CDCl₃)δ 7.49-7.42 (m, 6H), 7.36-7.25 (m, 6H), 7.29-7.21 (m, 3H), 3.97 (dd, J = 5.4, 4.0 Hz, 1H), 3.78 (s, 3H), 3.47 (s, 3H), 3.45-3.36 (m, 2H)。

step c:

stirring at room temperature under air atmosphere (2)S) To a solution of methyl (2-methoxy-3- (triphenylmethoxy) propionate (0.20 g, 0.53 mmol) in MeOH (3 mL) was added LiOH. H₂O (38 mg, 1.59 mmol) in H₂Solution in O (1 mL). The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated under reduced pressure to give (2) as an off-white solid S) -2-methoxy-3- (triphenylmethoxy) propionic acid (0.10 g, crude). The crude product was used without further purification in the subsequent step: c₂₃H₂₂O₄ [M + Na]⁺Calculated lcms (esi): 385, measured value 385.

EXAMPLE 49 intermediate 49 (tert-butyl 4- (1- (4, 5-dichloro-2-methoxyphenyl) -2-oxoethyl) piperidine-1-carboxylate)

Step a:

to a stirred mixture of (methoxymethyl) triphenylphosphonium chloride (12.36 g, 36.06 mmol) in THF (60 mL) at-78 deg.C under a nitrogen atmosphere was added dropwisenBuLi (10.30 mL, 25.75 mmol, 2.5M in hexane). The resulting mixture was stirred at-78 ℃ for 30 minutes under nitrogen. To the above mixture was added dropwise a solution of tert-butyl 4- (4, 5-dichloro-2-methoxybenzoyl) piperidine-1-carboxylate (2.00 g, 5.15 mmol) in THF (5 mL) at-78 deg.C over 5 minutes. The resulting mixture was stirred at-78 ℃ for an additional 2 hours. The reaction was quenched with saturated NH at 0 deg.C₄Aqueous Cl (80 mL) was quenched. The resulting mixture was extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (1/1) to give 4- [1- (4, 5-dichloro-2-methoxyphenyl) -2-methoxyvinyl ] as a pale yellow oil ]Piperidine-1-carboxylic acid tert-butyl ester (1.60 g, 59%) C₂₀H₂₇Cl₂NO₄ [M + H]⁺Lcms (esi) calculated value of (a): 416, 418 (3: 2), found 416, 418 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.09 (d, J =1.3 Hz, 1H), 6.91 (s, 1H), 5.87 (d, J = 1.3 Hz, 1H), 3.79 (s, 3H), 3.66 (s, 3H), 2.74-2.58 (m, 4H), 1.71-1.53 (m, 5H), 1.46 (d, J = 1.3 Hz, 9H)。

step b:

4- [ (ii) ((iii)) stirred downward at 0 ℃E) -1- (4, 5-dichloro-2-methoxyphenyl) -2-methoxyvinyl]To a solution of piperidine-1-carboxylic acid tert-butyl ester (1.80 g, 4.32 mmol) in 1, 4-dioxane (10 mL) was added dropwise aqueous HCl (6 mL)N10 mL). The resulting mixture was then warmed to room temperature and stirred for 3 hours. The resulting mixture was concentrated under reduced pressure. The crude resulting mixture was used without further purification in the subsequent step C₁₄H₁₇Cl₂NO₂ [M + H]⁺Calculated lcms (esi): 302, 304 (3: 2), measured values 302, 304 (3 : 2)

Step c:

to a stirred solution of 2- (4, 5-dichloro-2-methoxyphenyl) -2- (piperidin-4-yl) acetaldehyde (1.50 g, 4.96 mmol) in THF (15 mL) and saturated NaHCO at 0 deg.C₃Boc was added dropwise to the mixture in an aqueous solution (20 mL)₂O (1.62 g, 7.445 mmol). The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 4- [1- (4, 5-dichloro-2-methoxyphenyl) -2-oxoethyl group as a pale yellow oil ]Piperidine-1-carboxylic acid tert-butyl ester (1.30 g, 65%): C₁₉H₂₅Cl₂NO₄ [M + H]⁺Calculated lcms (esi): 402, 404 (3: 2), measured 402, 404 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 9.68 (d, J = 1.6 Hz, 1H), 7.13 (s, 1H), 7.00 (s, 1H), 4.04 (d, J = 13.6 Hz, 1H), 3.83 (s, 3H), 3.67 (dd, J = 8.9, 1.7 Hz, 1H), 2.82-2.71 (m, 1H), 2.66 (t, J = 12.6 Hz, 1H), 2.36-2.21 (m, 1H), 1.89 (dt, J = 13.3, 2.9 Hz, 1H), 1.67 (s, 1H), 1.45 (s, 9H), 1.41 (s, 1H), 1.26-1.16 (m, 1H), 1.10-0.95 (m, 1H)。

EXAMPLE 50 intermediate 50 (4- [ (4, 5-dichloro-2- [ [2- (trimethylsilyl) ethoxy ] methoxy ] phenyl) [ (2-methylpropane-2-sulfinyl) amino ] methyl ] -2, 2-dimethylpiperidine-1-carboxylic acid tert-butyl ester)

Step a:

to a solution of (methoxymethyl) triphenylphosphonium chloride (1508 mg, 4.40 mmol) in THF (7 mL) was added dropwise under a nitrogen atmosphere at-10 deg.CnBuLi (2.5 mL, 38.46 mmol, 2.5M in hexane). The solution was stirred at 0 ℃ for 1 hour. A solution of tert-butyl 2, 2-dimethyl-4-oxopiperidine-1-carboxylate (1 g, 4.40 mmol) in THF (5 mL) is then added dropwise at-20 ℃ under a nitrogen atmosphere. The mixture was stirred at room temperature for 15 hours.The reaction mixture was washed with saturated NH₄Aqueous Cl (30 mL) was quenched and extracted with EA (2X 20 mL). Passing the organic phase over anhydrous Na₂SO₄Dried, filtered and concentrated. The residue was subjected to silica gel chromatography and eluted with PE/EA (1/1) to give tert-butyl 4 (methoxymethylene) -2, 2-dimethylpiperidine-1-carboxylate (0.80 g, 71%): C as a colorless oil₁₄H₂₅NO₃ [M + H]⁺Calculated lcms (esi): 256, found 256; ¹H NMR (300 MHz, M ethanol) delta 5.97 (d,J = 24.0 Hz, 1H), 3.62-3.45 (m, 5H), 2.37-2.27 (m, 2H), 2.26-2.20 (m, 1H), 2.18 (s, 1H), 1.46 (d, J = 1.7 Hz, 9H), 1.38 (d, J = 2.7 Hz, 6H)。

step b:

to a solution of tert-butyl 4- (methoxymethylene) -2, 2-dimethylpiperidine-1-carboxylate (0.80 g, 3.13 mmol) in THF (10 mL) at room temperature was added aqueous HCl (4)N5 mL). The reaction mixture was stirred at 50 ℃ for 4 hours. The reaction mixture was then quenched with saturated NaHCO₃Basification of the aqueous solution to pH 9 followed by addition of Boc₂O (821 mg, 3.76 mmol). The mixture was stirred at room temperature for 1 hour. The resulting mixture was extracted with EA (2X 15 mL). Passing the organic phase over anhydrous Na₂SO₄Dried, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with PE/EA (2/1) to give tert-butyl 4-formyl-2, 2-dimethylpiperidine-1-carboxylate (360 mg, 48%): C as a colorless oil₁₃H₂₃NO₃ [M + H]⁺Calculated lcms (esi): 242, found value 242.

Step c':

to a stirred mixture of 2-bromo-4, 5-dichlorophenol (31.00 g, 128.15 mmol) and [2- (chloromethoxy) ethyl at room temperature]To a solution of trimethylsilane (32.00 g, 192.23 mmol) in DCM (100 mL) was added DIEA (49.70 g, 384.46 mmol). The resulting mixture was stirred at room temperature for 5 hours. The reaction was quenched with water (200 mL). The resulting mixture was extracted with DCM (3X 400 mL). The combined organic layers were washed with brine (3X 200 mL) and Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatographyDissolving, eluting with PE/EA (50/1), and obtaining [2- (2-bromo-4, 5-dichlorophenoxymethyloxy) ethyl ] in the form of light yellow oil]Trimethylsilane (44.00 g, 83%): 1H NMR (300 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.46 (s, 1H), 5.39 (s, 2H), 3.74 (t, J = 6.0 Hz, 2H), 0.79 (t, J = 6.0 Hz, 2H), -0.05 (s, 9H).

Step c:

to [2- (2-bromo-4, 5-dichlorophenoxymethyloxy) ethyl at-10 ℃ under nitrogen]Trimethylsilane (product of step c') (0.69 g, 1.86 mol) in THF (7 mL) was added dropwisei-PrMgCl (0.2 mL, 1.61 mmol, 2M in THF). The reaction mixture was stirred at-10 ℃ for 0.5 h under nitrogen. A solution of tert-butyl 4-formyl-2, 2-dimethylpiperidine-1-carboxylate (300 mg, 1.24 mmol) in THF (3 mL) is added dropwise to the resulting solution under a nitrogen atmosphere at-10 ℃. The reaction mixture was allowed to warm to room temperature and stirred under nitrogen for 2 hours. The resulting mixture was saturated with NH₄Aqueous Cl (40 mL) was quenched. The resulting mixture was extracted with EA (3X 10 mL). The organic phases were combined and passed over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with PE/EA (9/1) to give 4- [ (4, 5-dichloro-2- [ [2- (trimethylsilyl) ethoxy ] as a colorless oil ]Methoxy radical]Phenyl) (hydroxy) methyl]-2, 2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (0.20 g, 30%): C₂₅H₄₁Cl₂NO₅Si [M + H]⁺Lcms (esi) calculated value of (a): 534, 536 (3: 2), found 534, 536 (3: 2);¹H NMR (300 MHz, CDCl₃) δ 7.67 (s, 1H), 7.41 (s, 1H), 5.30 (s, 2H), 3.83-3.72 (m, 2H), 3.71-3.50 (m, 2H), 3.46-3.28 (m, 1H), 1.97-1.89 (m, 1H), 1.84-1.73 (m, 2H), 1.71-1.65 (m, 1H), 1.52 (d, J = 4.0 Hz, 6H), 1.49 (s, 9H), 1.40 (s, 2H), 0.04 (s, 9H)。

step d:

to 4- [ (4, 5-dichloro-2- [ [2- (trimethylsilyl) ethoxy) at room temperature]Methoxy radical]Phenyl) (hydroxy) methyl]-2, 2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (0.18 g, 0.34 mmol) in DCM (8 mL) was added three times to dess-martin reagent (0.14 g, 0.34 mmol)mmol). The reaction mixture was then stirred at room temperature for 2 hours. The reaction was saturated with Na₂SO₃The aqueous solution was quenched and then extracted with DCM (2X 10 mL). Passing the organic phase over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 4- [ (4, 5-dichloro-2- [ [2- (trimethylsilyl) ethoxy) as a colorless oil]Methoxy radical]Phenyl) carbonyl]Tert-butyl 2, 2-dimethylpiperidine-1-carboxylate (0.16 g, crude): C₂₅H₃₉Cl₂NO₅Si [M + H]⁺Calculated lcms (esi): 532, 534 (3: 2), found 532, 534 (3: 2).

Step e:

to 4- (4, 5-dichloro-2- [ [2- (trimethylsilyl) ethoxy) at room temperature]Methoxy radical]Benzoyl) -2, 2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (0.16 g, crude) in THF (10 mL) 2-methylpropane-2-sulfinamide (44 mg, 360 mmol) and Ti (OEt) were added in one portion ₄(0.90 g, 3.95 mmol). The reaction mixture was stirred at 70 ℃ for 15 hours under nitrogen atmosphere. The reaction mixture was quenched with water (50 mL). A solid was formed and filtered. The filtrate was extracted with EA (2X 40 mL). Combining the organic layers, passing over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 4- (4, 5-dichloro-2- [ [2- (trimethylsilyl) ethoxy) as a colorless oil]Methoxy radical]Phenyl) [ (2-methylpropane-2-sulfinyl) imino]Methyl radical]-tert-butyl 2, 2-dimethylpiperidine-1-carboxylate (0.20 g, crude): C₂₉H₄₈Cl₂N₂O₅SSi [M + Na]⁺Calculated lcms (esi): 657, 659 (3: 2), found 657, 659 (3: 2).

Step f:

under nitrogen atmosphere at room temperature to 4- [ (1)E) - (4, 5-dichloro-2- [ [2- (trimethylsilyl) ethoxy)]Methoxy radical]Phenyl) [ (2-methylpropane-2-sulfinyl) imino]Methyl radical](ii) -2, 2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.31 mmol) in MeOH (5 mL) NaBH was added in 5 portions₄ (58 mg, 1.54 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction mixture was saturated with NH₄Aqueous Cl solution (10)mL) was quenched. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE/EA (1/1) to give 4- [ (4, 5-dichloro-2- [ [2- (trimethylsilyl) ethoxy ] as a colorless oil ]Methoxy radical]Phenyl) [ (2-methylpropane-2-sulfinyl) amino]Methyl radical]Tert-butyl-2, 2-dimethylpiperidine-1-carboxylate (75 mg, 37%): C₂₉H₅₀Cl₂N₂O₅SSi [M + Na]⁺Calculated lcms (esi): 659, 661 (3: 2), found 659, 661 (3: 2).

Example 51 intermediate 51 (, (b)S)-N-((R) - (6- (allyloxy) -2, 3-dichlorophenyl) (piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide)

Step a:

to a stirred solution of 1, 2-dichloro-3-iodo-4- (prop-2-en-1-yloxy) benzene (1.25 g, 3.80 mmol) in THF (10 mL) at-65 deg.C under a nitrogen atmosphere was addedn-BuLi (1.2 mL, 3.80 mmol, 2.5M in hexane). Under nitrogen atmosphere, stirring at-65 deg.C for 30 min, and adding 4- [ [ (C) at-65 deg.C under nitrogen atmosphereS) -2-methylpropan-2-sulfinyl]Imino radical]Methyl radical]A solution of tert-butyl piperidine-1-carboxylate (0.80 g, 2.53 mmol) in THF (5 mL). After addition, the reaction mixture was stirred at-65 ℃ for an additional 1 hour under nitrogen atmosphere. The reaction was quenched with water (40 mL) at-65 ℃ and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and washed with PE/EA (7/1) to give 4- (7/1) as a pale yellow oil R) - (6- (allyloxy) -2, 3-dichlorophenyl) (((s))S) Tert-butylsulfinyl) amino) methyl) piperidine-1-carboxylic acid tert-butyl ester (0.80 g, 57%): C₂₄H₃₆Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 519, 521 (3: 2), found 519, 521 (3: 2); ¹H NMR (400 MHz, CDCL₃) δ 7.34 (d, J = 8.8 Hz, 1H), 6.79 (dd, J = 9.0, 4.9 Hz, 1H), 6.11-5.94 (m, 1H), 5.49-5.28 (m, 2H), 4.79 (t, J = 9.7 Hz, 1H), 4.68-4.50 (m, 3H), 4.36-3.91 (m, 3H), 2.77-2.47 (m, 2H), 2.40-2.29 (m, 1H), 2.18-2.02 (m, 1H), 1.46 (s, 9H), 1.34-1.22 (m, 1H), 1.04 (s, 9H)。

step b:

4- [ (ii) to stirring at room temperatureR) - [2, 3-dichloro-6- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]To a solution of tert-butyl piperidine-1-carboxylate (0.80 g, 1.54 mmol) in DCM (6 mL) was added TFA (1.5 mL). The reaction solution was stirred at room temperature for 1 hour. The resulting solution was diluted with water (6 mL) and saturated NaHCO₃The aqueous solution was neutralized to pH 8. The resulting mixture was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to obtain (A) as a pale yellow oilS)-N-[(R) - [2, 3-dichloro-6- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.60 g, 74%): C₁₉H₂₈Cl₂N₂O₂S [M + H]⁺Calculated lcms (esi): 419, 421 (3: 2), found 419, 421 (3: 2); ¹H NMR (400 MHz, CDCl₃) δ 7.36-7.31 (m, 1H), 6.81-6.76 (m, 1H), 6.11-5.95 (m, 1H), 5.49-5.34 (m, 2H), 4.81 (t, J = 10.0 Hz, 1H), 4.67-4.50 (m, 3H), 3.26 (d, J = 12.5 Hz, 1H), 3.08 (d, J = 12.4 Hz, 1H), 2.68-2.36 (m, 5H), 2.13 (t, J = 10.7 Hz, 1H), 1.04 (s, 9H)。

EXAMPLE 52 intermediate 52 (lithium 4-methyl-5-oxo-4, 5-dihydropyrazine-2-carboxylate)

Step a:

to stirred 5-oxo-4 at room temperatureH-pyrazine-2-carboxylic acid (3.00 g, 21.41 mmol) and K ₂CO₃ (14.8 g, 1.07 mol) in DMF (30 mL)Adding CH into the mixture₃I (15.2 g, 1.08 mol). The resulting mixture was stirred at 40 ℃ for 16 hours under nitrogen atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with EA (5X 60 mL). The combined organic layers were washed with brine (5X 80 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give methyl 4-methyl-5-oxopyrazine-2-carboxylate (2.50 g, 69%) as a dark brown solid₇H₈N₂O₃ [M + H]⁺Calculated lcms (esi): 169, measured value 169;¹H NMR (400 MHz, CD₃OD) δ 8.48 (s, 1H), 8.02 (s, 1H), 3.92 (s, 3H), 3.61 (s, 3H)。

step b:

to a stirred mixture of methyl 4-methyl-5-oxopyrazine-2-carboxylate (0.60 g, 3.57 mmol) in MeOH (7 mL) at room temperature was added LiOH (0.26 g, 10.71 mmol) in H₂Solution in O (1 mL). After stirring at room temperature for 20 hours, the resulting mixture was concentrated under reduced pressure. The crude product was used directly in the subsequent step without further purification. C₆H₆N₂O₃ [M + H]⁺Calculated lcms (esi): 155, found 155.

EXAMPLE 53 intermediate 53 (1-bromo-4-methyl-2- (prop-2-en-1-yloxy) benzene)

Step a:

to a stirred solution of 2-bromo-5-methylphenol (2.00 g, 10.69 mmol) in DMF (20 mL) at room temperature was added K₂CO₃(2.96 g, 21.41 mmol) and 3-bromoprop-1-ene (1.94 g, 16.04 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EA (50 mL) and water (50 mL). The aqueous solution was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (10/1) to give 1-bromo-4-carboxylic acid as a pale yellow oilMethyl-2- (prop-2-en-1-yloxy) benzene (1.29 g, 53%):¹H NMR (400 MHz, CD₃OD) δ 7.38 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 1.9 Hz, 1H), 6.69 (dd, J = 7.9, 2.0 Hz, 1H), 6.16-6.02 (m, 1H), 5.40-5.30 (m, 1H), 5.28-5.20 (m, 1H), 4.60 (d, J = 5.0 Hz, 2H), 2.32 (s, 3H)。

EXAMPLE 54 intermediate 54 (4- [ methoxy (methyl) carbamoyl ] -3-methylpiperidine-1-carboxylic acid tert-butyl ester)

Step a:

to stirred 3-methylpyridine-4-carboxylic acid (2.00 g, 14.58 mmol) and HCl (6) at room temperatureN,3 mL) in MeOH (15 mL) PtO was added₂(0.33 g, 1.46 mmol). At H₂ (50 atm) the resulting mixture was stirred at 50 ℃ for 12 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 3-methylpiperidine-4-carboxylic acid methyl ester HCl (2.30 g, 90%) C as a yellow oil₈H₁₅NO₂ [M + H]⁺Calculated lcms (esi): 158, measured value 158_； ¹H NMR (400 MHz, DMSO-d ₆) δ 3.86-3.69 (m, 2H), 3.64 (s, 3H), 3.15-2.90 (m, 2H), 2.83 (q, J = 5.7 Hz, 1H), 2.35-2.23 (m, 1H), 1.91-1.81 (m, 2H), 0.93 (d, J = 7.2 Hz, 3H)。

Step b:

to a stirred mixture of methyl 3-methylpiperidine-4-carboxylate (2.30 g, 14.63 mmol) and Et at room temperature₃Boc was added to a solution of N (2.96 g, 29.26 mmol) in THF (15 mL) and MeOH (30 mL)₂O (4.79 g, 21.95 mmol). The reaction solution was stirred at room temperature for 2 hours. The resulting mixture was diluted with EA (50 mL) and water (30 mL). The aqueous solution was extracted with EA (3X 20 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 20% aqueous ACN (plus 0.05% TFA) as a yellow oil1-tert-butyl-4-methyl-3-methylpiperidine-1, 4-dicarboxylate (2.90 g, 77% of two stages in total) was obtained (C)₁₃H₂₃NO₄ [M + H - 15]⁺Calculated lcms (esi): 243, measured value 243;¹H NMR (400 MHz, CDCl₃) δ 4.02 (s, 1H), 3.80 (dd, J = 13.3, 1.5 Hz, 1H), 3.70 (s, 3H), 3.31-2.81 (m, 2H), 2.62 (dt, J = 10.5, 4.3 Hz, 1H), 2.27-2.15 (m, 1H), 1.92-1.77 (m, 1H), 1.75-1.58 (m, 1H), 1.47 (s, 9H), 0.90 (dd, J = 6.8, 2.5 Hz, 3H)。

step c:

to a stirred solution of 1-tert-butyl 4-methyl 3-methylpiperidine-1, 4-dicarboxylate (2.70 g, 10.49 mmol) in MeOH (20 mL) at room temperature was added NaOH (0.83 g, 20.98 mmol) in H₂Solution in O (4 mL). The reaction mixture was stirred at room temperature for 12 hours and acidified to pH 3 with citric acid. The mixture was extracted with EA (3X 50 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 1- [ (tert-butoxy) carbonyl group as a yellow oil]3-methylpiperidine-4-carboxylic acid (1.30 g, 63%): C₁₂H₂₁NO₄ [M +Na]⁺Calculated lcms (esi): 266, measured value 266;¹H NMR (400 MHz, DMSO-d ₆) δ 12.24 (s, 1H), 3.88 (s, 1H), 3.70 (dd, J = 13.1, 3.6 Hz, 1H), 3.09-2.65 (m, 2H), 2.56 (dt, J = 10.0, 4.5 Hz, 1H), 2.19-2.08 (m, 1H), 1.65-1.49 (m, 2H), 1.39 (s, 9H), 0.80 (d, J = 6.9 Hz, 3H)。

step d:

to a stirred 1- [ (tert-butoxy) carbonyl group at room temperature]To a mixture of-3-methylpiperidine-4-carboxylic acid (1.10 g, 4.52 mmol) and HOBt (0.91 g, 6.78 mmol) in DMF (10 mL) was added EDCI (1.30 g, 6.78 mmol), Et ₃N (0.55 g, 5.43 mmol) and N,OMethoxy (methyl) amine (0.30 g, 4.97 mmol). The reaction solution was stirred at room temperature for 12 hours. The resulting solution was quenched with water (50 mL) at room temperature and extracted with EA (2X 50 mL). The combined organic layers were washed with brine (2X 50 mL) and dried over anhydrous Na₂SO₄And (5) drying. After the filtration, the mixture is filtered,the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with PE/EA (4/1) to give 4- [ methoxy (methyl) carbamoyl group as a colorless oil]3-methylpiperidine-1-carboxylic acid tert-butyl ester (1.00 g, 77%): C₁₄H₂₆N₂O₄ [M + H - 56]⁺Calculated lcms (esi): 231 found: 231;¹H NMR (400 MHz, CDCl₃) δ 4.17-3.89 (m, 2H), 3.86-3.76 (m, 1H), 3.73 (s, 3H), 3.29-3.13 (m, 4H), 3.13-2.94 (m, 2H), 2.24-2.09 (m, 1H), 2.06-1.87 (m, 1H), 1.48 (s, 9H), 0.93 (d, J = 7.0 Hz, 3H)。

EXAMPLE 55 intermediate 55 ((3S,4S) -rel-4- (2- (prop-2-en-1-yloxy) -4, 5-dichlorobenzoyl) -3-methylpiperidine-1-carboxylic acid tert-butyl ester; (3R,4S) -rel-4- (2- (prop-2-en-1-yloxy) -4, 5-dichlorobenzoyl) -3-methylpiperidine-1-carboxylic acid tert-butyl ester)

Step a:

to a stirred solution of 1-bromo-4, 5-dichloro-2- (prop-2-en-1-yloxy) benzene (2.12 g, 7.68 mmol) in THF (10 mL) at 0 deg.C under a nitrogen atmosphere was added dropwisei-PrMgCl (3.84 mL, 7.68 mmol, 2M in THF). The reaction was stirred at 0 ℃ for 30 minutes. Then 4- [ methoxy (methyl) carbamoyl group]A solution of tert-butyl (1.10 g, 3.84 mmol) 3-methylpiperidine-1-carboxylate in THF (8 mL) was added dropwise to the solution. After the addition, the resulting solution was stirred at 0 ℃ for an additional 1 hour. Reacting with saturated NH ₄Aqueous Cl (5 mL) was quenched. The reaction mixture was diluted with EA (30 mL) and water (30 mL), and the aqueous solution was then extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give a mixture of tert-butyl 4- (2- (allyloxy) -4, 5-dichlorobenzoyl) -3-methylpiperidine-1-carboxylate and tert-butyl 4- (4, 5-dichloro-2-hydroxybenzoyl) -3-methylpiperidine-1-carboxylate. The residue was dissolved in DMF (10 mL) and K was added at room temperature₂CO₃(0.88 g, 6.37 mmol) and allyl bromide (0.77 g, 6.37 mmol). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with EA (30 mL) and water (30 mL). The aqueous solution was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (6X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with PE/EA (10/1) to give 4- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl containing two cis enantiomers in the form of a pale yellow oil]3-methylpiperidine-1-carboxylic acid tert-butyl ester (0.90 g, 55%): C₂₁H₂₇Cl₂NO₄ [M + H - 56]⁺Calculated lcms (esi): 372, 374 (3: 2), measured 372, 374 (3: 2); ¹H NMR (400 MHz, CDCl₃) δ 7.67 (s, 1H), 7.06 (s, 1H), 6.15-5.97 (m, 1H), 5.52-5.38 (m, 2H), 4.69-4.54 (m, 2H), 4.25-4.03 (m, 1H), 4.01-3.86 (m, 1H), 3.68-3.52 (m, 1H), 3.12-2.94 (m, 1H), 2.91-2.76 (m, 1H), 2.24-2.10 (m, 1H), 2.01-1.84 (m, 1H), 1.76-1.55 (m, 1H), 1.55-1.39 (m, 9H), 0.85 (d, J =6.5 Hz, 3H)。

Separating 4- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl containing two trans enantiomers in the form of a pale yellow oil]-3-methylpiperidine-1-carboxylic acid tert-butyl ester) (0.12 g, 7%): C₂₁H₂₇Cl₂NO₄ [M + Na]⁺Lcms (esi) calculated value of (a): 450, 452 (3: 2), found 450, 452 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.68 (s, 1H), 7.07 (s, 1H), 6.11-5.93 (m, 1H), 5.44 (q, J = 11.2 Hz, 2H), 4.62 (d, J = 5.5 Hz, 2H), 4.19-4.10 (m, 1H), 3.92 (d, J = 13.0 Hz, 1H), 3.57 (d, J = 11.2 Hz, 1H), 3.01 (d, J = 13.1 Hz, 1H), 2.87-2.78 (m, 1H), 2.23-2.08 (m, 1H), 1.97-1.82 (m, 1H), 1.76-1.58 (m, 1H), 1.56-1.32 (m, 9H), 0.82-0.75 (m, 3H)。

EXAMPLE 56 intermediate 56 ((2)S) -1-methyl-5-oxopyrrolidine-2-carboxylic acid)

Step a:

stirred under nitrogen at 0 deg.C (2)S) To a solution of tert-butyl-5-oxopyrrolidine-2-carboxylate (0.50 g, 2.70 mmol) in THF (5 mL) was added NaH (0.22 g, 5.40 mmol, 60% in mineral oil). The resulting mixture was stirred at 0 ℃ for 30 minutes under nitrogen atmosphere. MeI (1.15 g, 8.10 mmol) was added dropwise to the above mixture at 0 ℃. The reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was quenched with water (40 mL) and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 50% aqueous ACN (plus 0.05% TFA) to give (2) as a pale yellow oilS) -1-methyl-5-oxopyrrolidine-2-carboxylic acid tert-butyl ester (0.34 g, 63%): C₁₀H₁₇NO₃ [2M + H]⁺Calculated lcms (esi): 399, measured value 399; ¹H NMR (400 MHz, CDCl₃) δ 4.09-3.92 (m, 1H), 2.87 (s, 3H), 2.57-2.43 (m, 1H), 2.43-2.24 (m, 2H), 2.13-1.98 (m, 1H), 1.50 (s, 9H)。

Step b:

stirring at room temperature (2)S) To a solution of tert-butyl (50 mg, 0.25 mmol) of-1-methyl-5-oxopyrrolidine-2-carboxylate in DCM (1 mL) was added TFA (1 mL). The reaction solution was stirred at room temperature for 2 hours. Concentrating the obtained solution under reduced pressure to obtain (2) as yellow oilS) -1-methyl-5-oxopyrrolidine-2-carboxylic acid (64 mg, crude), which was used without further purification in the next step: c₆H₉NO₃ [M + H]⁺Calculated lcms (esi): 144, found 144;¹H NMR (400 MHz, CDCl₃) δ 4.35-4.12 (m, 1H), 2.96 (s, 3H), 2.75-2.36 (m, 3H), 2.31-2.10 (m, 1H)。

EXAMPLE 57 intermediate 57 (bromo-5-chloro-4-ethyl-2- (prop-2-en-1-yloxy) benzene)

Step a:

to a stirred solution of 4-chloro-3-ethylphenol (3.00 g, 19.15 mmol) in DCM (20 mL) was added Br dropwise at room temperature₂(3.67 g, 22.96 mmol). The resulting solution was stirred at room temperature for 1 hour. The reaction was quenched with saturated Na at room temperature₂SO₃Aqueous solution (20 mL) was quenched and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 2-bromo-4-chloro-5-ethylphenol (4.50 g, crude) as a colorless oil, which was used in the next step without further purification:¹H NMR (400 MHz, CD₃OD) δ 7.42 (s, 1H), 6.83 (s, 1H), 2.65 (q, J = 7.5 Hz, 2H), 1.20 (t, J =7.5 Hz, 3H)。

step b:

to stirred 2-bromo-4-chloro-5-ethylphenol (4.50 g, 19.10 mmol) and K at room temperature ₂CO₃(5.28 g, 38.20 mmol) to a solution in DMF (40 mL) was added 3-bromoprop-1-ene (3.47 g, 28.68 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EA (50 mL) and water (50 mL). The aqueous solution was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (6X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (10/1) to give 1-bromo-5-chloro-4-ethyl-2- (prop-2-en-1-yloxy) benzene (2.40 g, 45% total of the two steps) as a colorless oil;¹H NMR (400 MHz, CD₃OD)δ 7.52 (s, 1H), 6.96 (s, 1H), 6.16-5.91 (m, 1H), 5.53-5.38 (m, 1H), 5.35-5.21 (m, 1H), 4.73-4.48 (m, 2H), 2.72 (q, J = 7.5 Hz, 2H), 1.23 (t, J =7.5 Hz, 3H)。

EXAMPLE 58 intermediate 58 (5- [ methoxy (methyl) carbamoyl)]-2-azabicyclo [ alpha ], [ alpha ] 2-aza ], [ alpha ] and [ alpha ], [ alpha ] a2.2.1]Heptane-2-carboxylic acid tert-butyl ester

Step a:

to a stirred 2- [ (tert-butoxy) carbonyl group at room temperature]-2-azabicyclo [ alpha ], [ alpha ] 2-aza ], [ alpha ] and [ alpha ], [ alpha ] a2.2.1]To a solution of heptane-5-carboxylic acid (0.50 g, 2.07 mmol) in DCM (5 mL) were added EDCI (0.60 g, 3.11 mmol) and HOBt (0.42 g, 3.11 mmol). After stirring at room temperature for 10 minutes, the mixture was added to the mixture at room temperatureN,OMethoxy (methyl) amine hydrochloride (0.30 g, 3.11 mmol) and Et₃N (0.63 g, 6.22 mmol). After stirring at room temperature for 5 hours, the resulting solution was diluted with water (30 mL) and extracted with DCM (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, extracted with 40% aqueous ACN (plus 0.05% TFA) to give 5- [ methoxy (methyl) carbamoyl group as a yellow oil]-2-azabicyclo [ alpha ], [ alpha ] 2-aza ], [ alpha ] and [ alpha ], [ alpha ] a2.2.1]Heptane-2-carboxylic acid tert-butyl ester (0.31g, 52%): C₁₄H₂₄N₂O₄ [M + H - 56]⁺Calculated lcms (esi): 229, found 229;¹H NMR (400 MHz, CDCl₃) δ 4.25 (s, 1H), 3.73 (s, 3H), 3.29 (dd, J = 9.9, 3.4 Hz, 1H), 3.22 (s, 3H), 3.17-2.98 (m, 1H), 2.98-2.81 (m, 1H), 2.75-2.67 (m, 1H), 2.03-1.84 (m, 2H), 1.81 (d, J = 10.1 Hz, 1H), 1.62 (d, J = 10.1 Hz, 1H), 1.49 (s, 9H)。

example 59 intermediate 59 (2-methyl-6-oxo-1)H-pyridine-3-carboxylic acid lithium salt

Step a:

to stirred 2-methyl-6-oxo-1 at room temperatureHTo a solution of ethyl-pyridine-3-carboxylate (0.10 g, 0.55 mmol) in MeOH (1 mL) was added LiOH H₂A solution of O (46 mg, 1.10 mmol) in water (0.5 mL). The resulting mixture was stirred at 40 ℃ for 1 hour. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure to give 2-methyl-6-oxo-1 as an off-white solidHLithium pyridine-3-carboxylate (0.15 g, crude), without further workThe purification was used directly in the next step: c₇H₇NO₃ [M + H]⁺Calculated lcms (esi): 154, found 154.

EXAMPLE 60 intermediate 60 (1- [2- (Oxocyclohexan-2-yloxy) ethyl ] -6-oxopyridine-3-carboxylic acid lithium)

Step a:

stirring of 6-oxo-1 at 0 ℃ under nitrogenHTo a solution of methyl-pyridine-3-carboxylate (0.50 g, 3.26 mmol) in DMF (5 mL) was added NaH (0.26 g, 6.53 mmol, 60% in mineral oil). The reaction mixture was stirred at 0 ℃ for 10 minutes. Then 2- (2-chloroethoxy) oxacyclohexane (1.61 g, 9.79 mmol) and NaI (97 mg, 0.65 mmol) were added to the mixture. After the addition, the reaction mixture was warmed to 70 ℃ and stirred for 5 hours. After cooling to room temperature, the resulting mixture was quenched with water (30 mL) at 0 ℃ and extracted with EA (3X 20 mL). The combined organic layers were washed with brine (6X 20 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the solution was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (2/1) to give 1- [2- (oxacyclohexan-2-yloxy) ethyl ] ethyl as a yellow oil]-6-oxopyridine-3-carboxylic acid methyl ester (0.50 g, 54%): C₁₄H₁₉NO₅ [M + H]⁺Lcms (esi) calculated value of (a): 282 measured value: 282;¹H NMR (400 MHz, CDCl₃) δ 8.83 (s, 1H), 8.18 (dt, J = 8.8, 2.1 Hz, 1H), 6.84 (d, J = 8.7 Hz, 1H), 4.81-4.49 (m, 3H), 4.17-3.93 (m, 1H), 3.93-3.77 (m, 4H), 3.68-3.45 (m, 2H), 1.95-1.46 (m, 6H)。

step b:

to a stirred 1- [2- (oxacyclohex-2-yloxy) ethyl radical at room temperature]To a solution of methyl (0.20 g, 0.711 mmol) 6-oxopyridine-3-carboxylate in MeOH (5 mL) was added LiOH H₂A solution of O (59 mg, 1.42 mmol) in water (0.5 mL). The resulting mixture was stirred at 40 ℃ for 1 hour. After cooling to room temperature, the resulting mixture was decompressedConcentrating to obtain 1- [2- (oxacyclohex-2-yloxy) ethyl]-lithium 6-oxopyridine-3-carboxylate (0.16 g, crude), which was used in the next step without further purification: c₁₃H₁₇NO₅ [M + Na]⁺Calculated lcms (esi): 290, found value 290.

EXAMPLE 61 lithium intermediate 61 (3- [ (tert-butoxycarbonyl) amino ] -2- [ [ (tert-butoxycarbonyl) amino ] methyl ] propionate)

Step a:

to a stirred mixture of methyl 3-amino-2- (aminomethyl) propionate dihydrochloride (0.50 g, 2.44 mmol) and Et at room temperature₃Boc was added to a solution of N (0.74 g, 7.31 mmol) in DCM (5 mL) ₂O (1.17 g, 5.36 mmol). The reaction solution was stirred at room temperature for 1 hour. The resulting solution was diluted with water (20 mL) and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 3- [ (tert-butoxycarbonyl) amino group as a yellow oil]-2- [ [ (tert-butoxycarbonyl) amino ] carbonyl]Methyl radical]Methyl propionate (1.00 g, crude), which was used in the next step without further purification: c₁₅H₂₈N₂O₆ [M + H]⁺Calculated lcms (esi): 333, measured value 333;¹H NMR (400 MHz, CDCl₃) δ 3.73 (s, 3H), 3.62-3.51 (m, 2H), 3.23 (dt, J = 13.6, 5.7 Hz, 2H), 2.80-2.64 (m, 1H), 1.55 (s, 9H), 1.46 (s, 9H)。

step b:

to a stirred 3- [ (tert-butoxycarbonyl) amino group at room temperature]-2- [ [ (tert-butoxycarbonyl) amino group]Methyl radical]To a solution of methyl propionate (1.00 g, 3.00 mmol) in MeOH (10 mL) was added LiOH. H₂A solution of O (0.25 g, 6.01 mmol) in water (1 mL). The resulting mixture was stirred at 40 ℃ for 1 hour. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure to give 3- [ (tert-butoxycarbonyl) amino group as an off-white solid]-2- [ [ (tert-butoxy)Alkylcarbonyl) amino]Methyl radical]Lithium propionate (1.00 g, crude), which was used in the next step without further purification: c₁₄H₂₆N₂O₆ [M + H]⁺Calculated lcms (esi): 319, found 319.

EXAMPLE 62 intermediate 62 (1-acetylpyrrolidine-3-carboxylic acid)

A, step a:

to 1- [ (tert-butoxy) carbonyl group at room temperature]Pyrrolidine-3-carboxylic acid (4.20 g, 19.51 mmol) and K₂CO₃ (5.40 g, 39.07 mmol) to a mixture in DMF (10 mL) was added (bromomethyl) benzene (5.00 g, 29.23 mmol). The resulting mixture was warmed to 50 ℃ and stirred for 1 hour. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with EA (3X 40 mL). The combined organic layers were washed with brine (5X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (2/1) to give 3-benzyl 1-tert-butylpyrrolidine-1, 3-dicarboxylate (2.77 g, 47%) as a pale yellow oil C₁₇H₂₃NO₄ [M + Na]⁺Calculated lcms (esi): 328, found value 328;¹H NMR (300 MHz, CD₃OD)δ 7.42-7.28 (m, 5H), 5.15 (s, 2H), 3.58-3.50 (m, 2H), 3.45-3.34 (m, 2H), 3.25-3.08 (m, 1H), 2.24-2.04 (m, 2H), 1.45 (s, 9H)。

step b:

to a stirred solution of 3-benzyl 1-tert-butylpyrrolidine-1, 3-dicarboxylate (2.77 g, 8.84 mmol) in DCM (5 mL) was added TFA (1 mL) at room temperature. The resulting solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure to give benzyl pyrrolidine-3-carboxylate (1.81 g, crude) as a pale yellow oil, which was used directly in the next step without further purification₁₂H₁₅NO₂ [M + H]⁺Calculated lcms (esi): 206, measured value 206.

Step c:

to a stirred mixture of benzyl pyrrolidine-3-carboxylate (1.81 g, 8.82 mmol) and Et at room temperature₃Acetic anhydride (1.40 g, 13.23 mmol) was added dropwise to a solution of N (2.70 g, 26.46 mmol) in DMF (20 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction was diluted with water (40 mL) and extracted with EA (3X 30 mL) at room temperature. The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with DCM/MeOH (10/1) to give benzyl 1-acetylpyrrolidine-3-carboxylate (1.60 g, 71% two steps in total) as a pale yellow oil₁₄H₁₇NO₃ [M + H]⁺Calculated lcms (esi): 248, measured value 248;¹H NMR (400 MHz, CD₃OD)δ 7.46-7.28 (m, 5H), 5.18 (d, J = 4.0 Hz, 2H), 3.75 (d, J = 6.9 Hz, 1H), 3.67 (d, J = 6.9 Hz, 1H), 3.63-3.54 (m, 1H), 3.54-3.40 (m, 1H), 3.32-3.18 (m, 1H), 2.34-2.10 (m, 2H), 2.05 (d, J = 3.5 Hz, 3H)。

step d:

a mixture of benzyl 1-acetylpyrrolidine-3-carboxylate (1.60 g, 6.47 mmol) and Pd/C (0.16 g, 1.50 mmol) in MeOH (15 mL) is stirred at room temperature under hydrogen (1.5 atm) for 1 h. The resulting mixture was filtered and the filter cake was washed with MeOH (3X 10 mL). The filtrate was concentrated under reduced pressure to give 1-acetylpyrrolidine-3-carboxylic acid (0.79 g, 62%) as a pale yellow oil, C₇H₁₁NO₃ [2M + Na]⁺Lcms (esi) calculated value of (a): 337, measured value 337;¹H NMR (300 MHz, CD₃OD)δ 3.73 (d, J = 7.0 Hz, 1H), 3.64 (d, J = 6.9 Hz, 1H), 3.61-3.35 (m, 2H), 3.27-3.06 (m, 1H), 2.31-2.10 (m, 2H), 2.06 (d, J = 5.2 Hz, 3H)。

example 63 intermediate 63 (, (ii)S)-N-[(S)-[1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl ]Piperidin-4-yl][ 5-fluoro-4-methyl-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]-2-methylpropane-2-sulfinamide)

A, step a:

to a stirred solution of 4-fluoro-3-methylphenol (2.00 g, 15.86 mmol) in DCM (20 mL) was added Br under air at room temperature₂(3.04 g, 19.02 mmol). The resulting mixture was stirred at room temperature for 1 hour under an air atmosphere. The reaction was incubated with saturated Na at room temperature₂SO₃Aqueous solution (1 mL) was quenched. The resulting mixture was extracted with EA (3X 50 mL). The combined organic layers were combined and concentrated under reduced pressure to give 2-bromo-4-fluoro-5-methylphenol, which was used in the next step without further purification:¹H NMR (400 MHz, CD₃OD) δ 7.15 (d, J = 8.9 Hz, 1H), 6.76 (d, J = 7.0 Hz, 1H), 2.17 (d, J = 2.1 Hz, 3H)。

step b:

to a stirred mixture of 2-bromo-4-fluoro-5-methylphenol (3.50 g, 17.07 mmol) and K at room temperature under an air atmosphere₂CO₃(4.72 g, 34.14 mmol) in DMF (30 mL) was added 3-bromoprop-1-ene (3.10 g, 25.61 mmol) dropwise. The resulting mixture was stirred at room temperature for 1 hour under an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (10/1) to give 1-bromo-5-fluoro-4-methyl-2- (prop-2-en-1-yloxy) benzene (2.30 g, 55%) as a colorless oil:¹H NMR (400 MHz, CD₃OD) δ 7.26 (d, J = 8.8 Hz, 1H), 6.95-6.85 (m, 1H), 6.15-6.01 (m, 1H), 5.48 (dq, J = 17.3, 1.9 Hz, 1H), 5.28 (dq, J = 10.6, 1.6 Hz, 1H), 4.62-4.54 (m, 2H), 2.24 (d, J = 2.1 Hz, 3H)。

step c:

to a stirred solution of 1-bromo-5-fluoro-4-methyl-2- (prop-2-en-1-yloxy) benzene (0.11 g, 0.435 mmol) in THF (3 mL) at-78 deg.C under a nitrogen atmosphere was added dropwise nBuLi (0.17 mL, 0.425 mmol). The reaction was stirred at-78 ℃ for 30 minutes. Then will be (A)S)-N-[[1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl]Methylene group]-2-methylpropan-2-ylideneSulfonamide (0.10 g, 0.29 mmol) was added to the mixture. The resulting solution was stirred at-78 ℃ for 2 hours. To react with NH₄Cl (1 mL) was quenched. The resulting mixture was diluted with EA (30 mL) and water (30 mL), and the aqueous solution was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC, eluting with PE/EA (1/4), to give (a) as a colorless oilS)-N-[(S)-[1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical][ 5-fluoro-4-methyl-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]-2-methylpropane-2-sulfinamide (40 mg, 27%): C₂₆H₃₉FN₂O₅S [M + H]⁺Calculated lcms (esi): 511, found value 511.

Example 64 intermediate 64 (N- [ (4, 5-dichloro-2-hydroxyphenyl) (pyridin-4-yl) methyl]Acetamide, N- [ (2, 3-dichloro-6-hydroxyphenyl) (pyridin-4-yl) methyl]Acetamide)

Step a:

3, 4-dichlorophenol (2.00 g, 12.27 mmol), pyridine-4-carbaldehyde (1.31 g, 12.27 mmol), acetamide (0.87 g, 14.72 mmol), FeCl ₃ (0.30 g, 1.84 mmol) of the mixture was stirred at 110 ℃ for 1 hour. After cooling to room temperature, the resulting mixture was diluted with EA (200 mL). The mixture was stirred for 20 minutes and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with DCM/MeOH (10/1) to give the crude product. The crude product was purified by preparative TLC eluting with DCM/MeOH (10/1) to afford it as a light brown solidN- [ (4, 5-dichloro-2-hydroxyphenyl) (pyridin-4-yl) methyl]Acetamide and N- [ (2, 3-dichloro-6-hydroxyphenyl) (pyridin-4-yl) methyl]Mixture of acetamides (0.12 g, 3%): C₁₄H₁₂Cl₂N₂O₂ [M + H]⁺Calculated lcms (esi): 311, 313 (3: 2), found 311, 313 (3: 2).

EXAMPLE 65 intermediate 65 (6- [ methoxy (methyl) carbamoyl)]-3-azabicyclo [ 2 ]3.1.1]Heptane-3-carboxylic acid tert-butyl ester

Step a:

to the stirred 3-tert-butyl 6-methyl 3-azabicyclo [ 2 ] at room temperature3.1.1]To a solution of heptane-3, 6-dicarboxylate (0.40 g, 1.57 mmol) in MeOH (4 mL) was added KOH (0.18 g, 3.13 mmol) in H₂Solution in O (1 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction was acidified to pH 3 with citric acid (30 mL). The resulting mixture was extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 3- [ (tert-butoxy) carbonyl group as a pale yellow oil]-3-azabicyclo [ 2 ]3.1.1]Heptane-6-carboxylic acid (0.40 g, crude), which was used in the next step without further purification: c₁₂H₁₉NO₄ [M + Na]⁺Calculated lcms (esi): 264, measured value 264;¹H NMR (400 MHz, CD₃OD) δ 3.92-3.79 (m, 1H), 3.64-3.56 (m, 1H), 3.43-3.32 (m, 1H), 3.11-3.02 (m, 1H), 2.72-2.57 (m, 2H), 2.56-2.43 (m, 1H), 2.13-2.03 (m, 1H), 1.47 (d, J = 11.9 Hz, 9H), 1.38-1.29 (m, 1H)。

step b:

to a stirred 3- [ (tert-butoxy) carbonyl group at room temperature]-3-azabicyclo [ 2 ]3.1.1]To a solution of heptane-6-carboxylic acid (0.40 g, 1.66 mmol), HOBt (0.34 g, 2.49 mmol) and EDCI (0.48 g, 2.49 mmol) in DCM (5 mL) was addedN,O-Methoxy (methyl) amine hydrochloride (0.24 g, 2.49 mmol) and Et₃N (0.50 g, 4.97 mmol). After stirring at room temperature for 1 hour, the reaction was quenched with water (50 mL) at room temperature and extracted with EA (3X 40 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 70% aqueous ACN (plus 0.05% TFA) toThe 6- [ methoxy (methyl) carbamoyl radical is obtained in the form of a pale yellow oil]-3-azabicyclo [ 2 ]3.1.1]Heptane-3-carboxylic acid tert-butyl ester (0.36 g, 81% in two stages in total): C₁₄H₂₄N₂O₄ [M + H - 56]⁺Calculated lcms (esi): 229, found 229;¹H NMR (400 MHz, CDCl₃) δ 4.04 (d, J = 11.8 Hz, 1H), 3.88-3.76 (m, 1H), 3.70 (s, 3H), 3.52-3.36 (m, 2H), 3.19 (s, 3H), 3.13-3.05 (m, 1H), 2.86-2.79 (m, 1H), 2.78-2.66 (m, 1H), 2.09 (q, J = 6.9 Hz, 1H), 1.48 (s, 9H), 1.34 (d, J = 9.4 Hz, 1H)。

example 66 intermediate 66 ((3)R) -3- [ methoxy (methyl) carbamoyl ]Pyrrolidine-1-carboxylic acid tert-butyl ester

Step a:

stirring at room temperature (3)R) A solution of (E) -1- (tert-butoxycarbonyl) pyrrolidine-3-carboxylic acid (2.50 g, 11.61 mmol), HOBt (2.35 g, 17.39 mmol) and EDCI (3.34 g, 17.42 mmol) in DCM (20 mL) was addedN,OMethoxy (methyl) amine hydrochloride (1.70 g, 17.42 mmol) and Et₃N (2.35 g, 23.23 mmol). The reaction solution was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (50 mL) and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 40% aqueous ACN (plus 0.05% TFA) to give (3) as a colorless oilR) -3- [ methoxy (methyl) carbamoyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (2.50 g, 67%): C₁₂H₂₂N₂O₄ [M + H - 56]⁺Calculated lcms (esi): 203, measured value 203;¹H NMR (400 MHz, CDCl₃) δ 3.73 (s, 3H), 3.71-3.50 (m, 2H), 3.50-3.30 (m, 3H), 3.22 (s, 3H), 2.23-2.00 (m, 2H), 1.48 (s, 9H)。

example 67 intermediate 67 ((3)S) -3- [ methoxy (methyl) aminoRadical formyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester

Step a:

stirring at room temperature (3)S) A solution of (E) -1- (tert-butoxycarbonyl) pyrrolidine-3-carboxylic acid (2.50 g, 11.61 mmol), HOBt (2.35 g, 17.39 mmol) and EDCI (3.34 g, 17.42 mmol) in DCM (20 mL) was added N,OMethoxy (methyl) amine hydrochloride (1.70 g, 17.42 mmol) and Et₃N (2.35 g, 23.23 mmol). The reaction solution was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (50 mL) and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 50% aqueous ACN (plus 0.05% TFA) to give (3) as a colorless oilS) -3- [ methoxy (methyl) carbamoyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (2.50 g, 67%): C₁₂H₂₂N₂O₄ [M + H - 56]⁺Calculated lcms (esi): 203, measured value 203;¹H NMR (400 MHz, CDCl₃) δ 3.74 (s, 3H), 3.66 (t, J = 9.1 Hz, 1H), 3.61-3.53 (m, 1H), 3.51-3.30 (m, 3H), 3.22 (s, 3H), 2.20-2.03 (m, 2H), 1.48 (s, 9H)。

EXAMPLE 68 intermediate 68 (lithium 5-chloro-6-oxo-1, 6-dihydropyridine-3-carboxylate)

Step a:

to stirred 5-chloro-6-oxo-1 at room temperatureH-pyridine-3-carboxylic acid methyl ester (0.20 g, 1.07 mmol) in MeOH (2 mL) and H₂LiOH. H was added to the solution in O (1 mL)₂O (90 mg, 2.13 mmol). The resulting mixture was warmed to 40 ℃ and stirred for 1 hour. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure to give 5-chloro-6-oxo-1, 6-dihydro-l-as a pale yellow solidLithium pyridine-3-carboxylate (0.20 g, crude), which was used without further purification in the next step: c₆H₄ClNO₃ [M + H]⁺Calculated lcms (esi): 174, 176 (3: 1), found 174, 176 (3: 1).

EXAMPLE 69 intermediate 69 (lithium 6- (hydroxymethyl) pyridine-3-carboxylate)

A, step a:

to a stirred solution of methyl 6- (hydroxymethyl) pyridine-3-carboxylate (0.20 g, 1.20 mmol) in MeOH (2 mL) and H at room temperature₂LiOH. H was added to the mixture in O (1 mL)₂O (0.10 g, 2.39 mmol). The resulting mixture was stirred at 40 ℃ for 1 hour. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure to give lithium 6- (hydroxymethyl) pyridine-3-carboxylate (0.20 g, crude) as a pale yellow solid, which was used in the next step without further purification: c₇H₇NO₃ [M + H]⁺Calculated lcms (esi): 154, found 154.

EXAMPLE 70 intermediate 70 (3- [ (4-methoxyphenyl) methyl ] -2-oxo-1, 3-oxazinane-5-carboxylic acid)

Step a:

to a stirred mixture of ethyl 2- (hydroxymethyl) prop-2-enoate (1.00 g, 7.68 mmol) in MeOH (20 mL) was added dropwise (4-methoxyphenyl) methylamine (1.16 g, 8.46 mmol) at room temperature. The resulting solution was stirred at room temperature for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with DCM/MeOH (10/1) to give 3-hydroxy-2- ([ [ (4-methoxyphenyl) methyl) as a pale yellow oil]Amino group]Ethyl methyl) propionate (1.60 g, 78%) C ₁₄H₂₁NO₄ [M + H]⁺Lcms (esi) calculated value of (a): 268, found value 268;¹H NMR (400 MHz, CDCl₃) δ 7.24 (d, J = 8.1 Hz, 2H), 6.93-6.85 (m, 2H), 4.24-4.15 (m, 1H), 4.06-3.94 (m, 2H), 3.82 (s, 3H), 3.75 (s, 2H), 3.38-3.08 (m, 2H), 2.98-2.89 (m, 1H), 2.77-2.66 (m, 1H), 1.29 (td, J = 7.2, 1.4 Hz, 3H)。

step b:

stirred 3-hydroxy-2- ([ [ (4-methoxyphenyl) methyl) at 0 ℃ C]Amino group]To a solution of ethyl methyl) propionate (0.70 g, 2.62 mmol) in DCM (80 mL) was added CDI (0.42 g, 2.62 mmol) in portions. The resulting mixture was allowed to warm to room temperature and stirred for 3 hours. The resulting solution was concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with PE/EA (1/2) to give 3- [ (4-methoxyphenyl) methyl group as a pale yellow oil]-2-oxo-1, 3-oxazinane-5-carboxylic acid ethyl ester (0.60 g, 55%): C₁₅H₁₉NO₅ [M + H]⁺Calculated lcms (esi): 294, measured value 294;¹H NMR (400 MHz, CDCl₃) δ 7.27 (d, J = 9.4 Hz, 2H), 6.92-6.87 (m, 2H), 4.64-4.36 (m, 3H), 4.23-4.11 (m, 1H), 3.83 (s, 3H), 3.73 (s, 2H), 3.54-3.45 (m, 1H), 3.43-3.35 (m, 1H), 3.10-2.99 (m, 1H), 1.26 (t, J = 7.2 Hz, 3H)。

step c:

to a stirred 3- [ (4-methoxyphenyl) methyl group at room temperature]-mixture of ethyl 2-oxo-1, 3-oxazinane-5-carboxylate (0.40 g, 1.36 mmol) in 1, 4-dioxane (3 mL) aqueous HCl (4) was addedN3.00 mL). The resulting mixture was stirred at 50 ℃ for 3 hours. The resulting mixture was concentrated under reduced pressure to give 3- [ (4-methoxyphenyl) methyl group as an off-white solid]-2-oxo-1, 3-oxazinane-5-carboxylic acid (0.40 g, crude), which was used in the next step without further purification: c₁₃H₁₅NO₅ [M + H]⁺Calculated lcms (esi): 266, measured value 266;¹H NMR (400 MHz, CD₃OD) δ 7.31-7.22 (m, 2H), 6.94-6.89 (m, 2H), 4.58-4.40 (m, 4H), 3.80 (s, 3H), 3.57-3.41 (m, 2H), 3.16-3.08 (m, 1H)。

example 71 intermediate 71 (3- (hydroxymethyl) azetidin-3-ol trifluoroacetic acid)

A, step a:

to a stirred 1- [ (tert-butoxy) carbonyl group at-10 ℃ under a nitrogen atmosphere]-3-Methylazetidine-3-carboxylic acid (0.45 g, 2.09 mmol) in THF (4 mL) was added BH dropwise₃THF (6 mL, 6.27 mmol, 1M in THF). The reaction solution was warmed to 0 ℃ under nitrogen atmosphere and stirred for 12 hours. Reaction with H at 0 deg.C₂O (20 mL) quench. The resulting mixture was concentrated under reduced pressure to give 3- (hydroxymethyl) -3-methylazetidine-1-carboxylic acid tert-butyl ester (0.45 g, crude) as an off-white semi-solid:¹H NMR (400 MHz, CDCl₃) δ 4.35-4.22 (m, 2H), 4.17-3.97 (m, 4H), 1.47 (s, 9H)。

step b:

to a stirred solution of tert-butyl 3-hydroxy-3- (hydroxymethyl) azetidine-1-carboxylate (0.45 g, 2.24 mmol) in DCM (4 mL) at 0 deg.C was added TFA (1 mL). The reaction solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure to give 3- (hydroxymethyl) azetidin-3-ol trifluoroacetic acid (0.35 g, crude): C as a colorless oil₄H₉NO₂ [M + H]⁺Calculated lcms (esi): 104, found: 104.

EXAMPLE 72 intermediate 72 (1-bromo-5-chloro-4-cyclopropyl-2- (prop-2-en-1-yloxy) benzene)

Step a:

to a stirred solution of 4-chloro-3-iodophenol (1.00 g, 3.90 mmol) and cyclopropylboronic acid (0.67 g, 7.86 mmol) in 1, 4-dioxane (15 mL) was added Na at room temperature under a nitrogen atmosphere ₂CO₃(1.20 g, 11.71 mmol) in water (5 mL) and Pd (dppf) Cl₂ CH₂Cl₂(0.30 g, 0.39 mmol). The reaction mixture was degassed with nitrogen and stirred at 90 ℃ for 24 hours under nitrogen atmosphere. After cooling to room temperatureThe reaction mixture was diluted with water (30 mL) and the resulting mixture was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (4/1) to give 4-chloro-3-cyclopropylphenol (0.48 g, 72%) as a colorless oil:¹H NMR (400 MHz, CD₃OD) δ 7.13 (d, J = 8.5 Hz, 1H), 6.56 (dd, J = 8.7, 2.9 Hz, 1H), 6.39 (d, J = 2.9 Hz, 1H), 2.19-2.09 (m, 1H), 1.02-0.95 (m, 2H), 0.67-0.59 (m, 2H)。

step b:

to a stirred solution of 4-chloro-3-cyclopropylphenol (1.00 g, 5.93 mmol) in DCM (10 mL) was added Br dropwise at room temperature₂(1.14 g, 7.13 mmol). The reaction mixture was stirred at room temperature for 1 hour. The resulting solution was taken up with saturated Na at room temperature₂SO₃Aqueous solution (10 mL) was quenched. The resulting mixture was diluted with water (20 mL) and extracted with EA (3X 20 mL). The combined organic layers were washed with brine (2X 15 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give crude 2-bromo-4-chloro-5-cyclopropylphenol (0.94 g) as a colorless oil:¹H NMR (400 MHz, CDCl₃) δ 8.04 (s, 1H), 6.61 (s, 1H), 2.21-2.03 (m, 1H), 1.10-0.98 (m, 2H), 0.70-0.61(m, 2H)。

step c:

to a solution of 2-bromo-4-chloro-5-cyclopropylphenol (0.94 g, 3.79 mmol) in DMF (10 mL) was added dropwise K at room temperature under an air atmosphere ₂CO₃(1.00 g, 7.59 mmol) and 3-bromoprop-1-ene (0.69 g, 5.69 mmol). The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (80 mL) and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 50 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (10/1) to give 1-bromo-5-chloro-4-cyclopropyl-2- (prop-2-en-1-yloxy) benzene (0.27 g, 25%) as a yellow oil:¹H NMR (400 MHz, CD₃OD) δ 7.53 (s, 1H), 6.60 (s, 1H), 6.12-6.01 (m, 1H), 5.55-5.42 (m, 1H), 5.33-5.26 (m, 1H), 4.61 (dt, J = 5.0, 1.7 Hz, 2H), 2.20-2.12 (m, 1H), 1.09-0.96 (m, 2H), 0.77-0.68 (m, 2H)。

example 73 intermediate 73 (, (b)N,N-Diethylcarbamic acid 4-chloro-3-fluoro-5-methylphenyl ester)

Step a:

NBS (71.11 g, 399.53 mmol) was added in 5 portions to a solution of 2-fluoro-6-methylaniline (50.00 g, 399.53 mmol) in DMF (300 mL) at 0 ℃. The reaction was then allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was poured into water (3L) and extracted with EA (3X 500 mL). The combined organic layers were washed with brine (5X 200 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 4-bromo-2-fluoro-6-methylaniline (90.00 g, crude) as a pale yellow oil:¹H NMR (400 MHz, CDCl₃) δ 7.05 (dd, J = 10.1, 2.2 Hz, 1H), 7.00 (dt, J = 2.1, 1.1 Hz, 1H), 3.63 (s, 2H), 2.18 (s, 3H)。

step b:

to 4-bromo-2-fluoro-6-methylaniline (80.00 g, 392.08 mmol) in aqueous HCl (12 ℃ C.) at 0 deg.C N600 mL) was added dropwise to NaNO₂ (31.92 g, 462.65 mmol) in H₂Solution in O (200 mL). The reaction mixture was stirred at 0 ℃ for 1 hour. To the resulting mixture was added dropwise copper chloride (116.83 g, 1180.15 mmol) 20 times at 0 ℃. After the addition, the resulting mixture was stirred at room temperature for 0.5 hour and then at 50 ℃ for 12 hours. The mixture was saturated with Na₂CO₃The aqueous solution was neutralized to pH 8. The resulting mixture was diluted with water (1L) and extracted with EA (3X 500 mL). The combined organic layers were washed with brine (2X 500 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with PE/EA (20/1) to give 5-bromo-2-chloro-1-fluoro-3-methylbenzene (41.00 g,47%): ¹H NMR (400 MHz, CDCl₃) δ 7.24-7.21 (m, 1H), 7.19 (dd, J = 8.0, 2.3 Hz, 1H), 2.40 (s, 3H)； ¹⁹F NMR (376 MHz, CDCl₃) δ -111.76.

step c:

to 5-bromo-2-chloro-1-fluoro-3-methylbenzene (41.00 g, 183.47 mmol) in DMSO (320 mL) and H under a nitrogen atmosphere₂To a solution in O (80 mL)N,NBis (4-hydroxy-2, 6-dimethylphenyl) oxalamide (3.01 g, 9.17 mmol), LiOH. H₂O (16.17 g, 385.29 mmol) and N¹,N ²Bis (4-hydroxy-2, 6-dimethylphenyl) oxamide (2.40 g, 9.17 mmol). The suspension was degassed under nitrogen atmosphere. The reaction was then stirred for 16 hours at 80 ℃. After cooling to room temperature, the resulting mixture was taken up in aqueous HCl (2) N200 mL), diluted with water (2L) and extracted with EA (3X 500 mL). The combined organic layers were washed with brine (5X 300 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with PE/EA (2/1) to give 4-chloro-3-fluoro-5-methylphenol (30.00 g, 92%) C as a colorless oil₇H₆ClFO [M - H]^-Calculated lcms (esi): 159, 161 (3: 1), found 159, 161 (3: 1);¹H NMR (400 MHz, CDCl₃) δ 6.60-6.50 (m, 2H), 5.00 (s, 1H), 2.36 (s, 3H)； ¹⁹F NMR (376 MHz, CDCl₃) δ -112.60.

step d:

to 4-chloro-3-fluoro-5-methylphenol (37.00 g, 230.43 mmol), Et at 0 deg.C over 15 min under nitrogen₃A solution of N (95.90 g, 949.57 mmol) and DMAP (56.30 g, 460.86 mmol) in DCM (500 mL) was added dropwise to diethyl carbamoyl chloride (37.49 g, 276.51 mmol). The reaction solution was stirred at room temperature under nitrogen atmosphere for 12 hours. The resulting solution was diluted with water (500 mL) and extracted with DCM (2X 250 mL). The combined organic layers were washed with brine (2X 200 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (5/1) to give a colorless oilN,N4-chloro-3-fluoro-5-methylphenyl (40.00 g, 82%) diethyl carbamate C₁₂H₁₅ClFNO₂ [M + H]⁺Lcms (esi) calculated value of (a): 260, 262 (3: 1), found 260, 262 (3: 1); ¹H NMR (400 MHz, CDCl₃) δ 6.89-6.85 (m, 2H), 73.46-3.37 (m, 4H), 2.40 (s, 3H), 1.28-1.20 (m, 6H)。

EXAMPLE 74 intermediate 74 (5-chloro-1-methyl-6-oxopyridine-3-carboxylic acid)

A, step a:

to stirred 5-chloro-6-oxo-1 at room temperatureH-pyridine-3-carboxylic acid methyl ester (1.00 g, 5.33 mmol) and K₂CO₃(2.21 g, 15.99 mmol) in DMF (6 mL) MeI (3.78 g, 26.65 mmol) was added dropwise. The reaction mixture was stirred at 40 ℃ for 5 hours. The reaction mixture was diluted with water (50 mL). The resulting mixture was extracted with EA (3X 10 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give methyl 5-chloro-1-methyl-6-oxopyridine-3-carboxylate (0.98 g, 90%): C as a yellow solid₈H₈ClNO₃ [M + H]⁺Calculated lcms (esi): 202, 204 (3: 1), measured values 202, 204 (3: 1); ¹H NMR (400 MHz, CD₃OD) δ 8.46 (d, J = 2.3 Hz, 1H), 8.13 (d, J = 2.3 Hz, 1H), 3.88 (s, 3H), 3.68 (s, 3H)。

step b:

to a stirred mixture of methyl 5-chloro-1-methyl-6-oxopyridine-3-carboxylate (0.50 g, 2.48 mmol) in MeOH (3 mL, 74.09 mmol) under an air atmosphere at 0 deg.C was added aqueous NaOH (1N3 mL). The resulting mixture was stirred at room temperature for 3 hours. The mixture was washed with aqueous HCl (1)N0.5 mL) was acidified to pH 6. The precipitated solid was collected by filtration and washed with MeOH (2X 2 mL) to give 5-chloro-1-methyl-6-oxopyridine-3-carboxylic acid (0.45 g, 87%) as an off-white solid C ₇H₆ClNO₃ [M + H]⁺Lcms (esi) calculated value of (a): 188, 190 (3: 1), found 188, 190 (3: 1); ¹H NMR (400 MHz, DMSO-d ₆) δ 13.06 (s, 1H), 8.51 (d, J =2.3 Hz, 1H), 7.99 (d, J = 2.3 Hz, 1H), 3.58 (s, 3H)。

example 75 intermediate 75 (, (b)S)-N-((R) - (2- (allyloxy) -5-chloro-4- (trifluoromethyl) phenyl) (piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide)

A, step a:

to a stirred solution of 4-chloro-3- (trifluoromethyl) phenol (3.00 g, 15.26 mmol) in DCM (30 mL) was added Br dropwise at room temperature₂(2.44 g, 15.26 mmol). The resulting mixture was stirred at room temperature under nitrogen for 4 hours. At 0 deg.C, the reaction was saturated with Na₂S₂O₃Aqueous solution (100 mL) was quenched. The resulting mixture was extracted with EA (4X 200 mL). The combined organic layers were washed with brine (2X 200mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 2-bromo-4-chloro-5- (trifluoromethyl) phenol as a yellow oil. The crude product was used without further purification in the subsequent step: c₇H₃BrClF₃O [M - H]⁺Calculated lcms (esi): 273, 275 (2: 3), found: 273, 275 (2: 3).

Step b:

to stirred 2-bromo-4-chloro-5- (trifluoromethyl) phenol (crude) and K at room temperature₂CO₃ (4.01 g, 29.04 mmol) to a mixture in DMF (20 mL) was added allyl bromide (2.64 g, 21.78 mmol) dropwise. The resulting mixture was stirred at 40 ℃ for 16 hours. After cooling to room temperature, the resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EA (3X 60 mL). The combined organic layers were washed with brine (6X 60 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography,eluting with PE/EA (4/1), gave 1-bromo-5-chloro-2- (prop-2-en-1-yloxy) -4- (trifluoromethyl) benzene (1.00 g, 22%) as a pale yellow oil:¹H NMR (400 MHz, CDCl₃) δ 7.72 (s, 1H), 7.17 (s, 1H), 6.15-6.00 (m, 1H), 5.59-5.34 (m, 2H), 4.67 (dt, J = 5.1, 1.7 Hz, 2H)。

step c:

to a stirred solution of 1-bromo-5-chloro-2- (prop-2-en-1-yloxy) -4- (trifluoromethyl) benzene (0.94 g, 2.97 mmol) in THF (100 mL) at-90 deg.C under a nitrogen atmosphere was added dropwisenBuLi (1.19 mL, 2.97 mmol, 2.5M in hexane). The resulting mixture was stirred at-90 ℃ for 40 minutes under nitrogen. Dropwise adding 4- [ [ (C) (under nitrogen atmosphere) to the stirred solution at-90 deg.CS) -2-methylpropan-2-sulfinyl]Imino radical]Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester (0.94 g, 2.97 mmol). The resulting mixture was stirred at-90 ℃ for 1 hour under nitrogen. The reaction was quenched with water (150 mL) at-90 ℃. The resulting mixture was extracted with EA (3X 100 mL). The combined organic layers were washed with brine (3X 100 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography using a column containing 20 mmol/L NH₄HCO₃Eluting with 75% ACN aqueous solution to obtain 4- [ (II) in the form of light yellow oilR) - [ 5-chloro-2- (prop-2-en-1-yloxy) -4- (trifluoromethyl) phenyl ]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 47%). C₂₅H₃₆ClF₃N₂O₄S [M + H]⁺Calculated lcms (esi): 553, 555 (3: 1), found 553, 555 (3: 1).

Step d:

4- [ (ii) at room temperature to stirring under air atmosphereR) - [ 5-chloro-2- (prop-2-en-1-yloxy) -4- (trifluoromethyl) phenyl][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]To a solution of tert-butyl piperidine-1-carboxylate (1.00 g, 1.81 mmol) in DCM (10 mL) was added TFA (2.5 mL) dropwise. The final reaction mixture was stirred at room temperature for 1 hour. The mixture was washed with saturated NaHCO₃The aqueous solution was acidified to pH 8. The resulting mixture was extracted with EA (3X 20 mL). Will mergeThe organic layer was washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to obtain (A) as a pale yellow oilS)-N-((R) - (2- (allyloxy) -5-chloro-4- (trifluoromethyl) phenyl) (piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (0.94 g, 87%): C₂₀H₂₈ClF₃N₂O₂S [M + H]⁺Calculated lcms (esi): 453, 455 (3: 1), found 453, 455 (3: 1).

EXAMPLE 76 intermediate 76 (2, 3-dihydroxybutyric acid)

Step a:

to a stirred solution of crotonic acid (5.00 g, 58.08 mmol) and 3-chlorobenzene-1-peroxoformic acid (9.00 g, 52.27 mmol) in chloroform (60.00 mL) was added H portionwise at room temperature ₂O (120 mL). The resulting mixture was stirred at room temperature for 16 hours. Separating the two layers, and subjecting the chloroform layer to H₂O (3X 60 mL). The aqueous layer was concentrated under reduced pressure. The residue was dissolved in water (50 mL) and stirred at 50 ℃ for 16 hours. The resulting solution was concentrated under reduced pressure to give 2, 3-dihydroxybutyric acid (1.00 g, 15%) as an off-white solid:¹H NMR (400 MHz, DMSO-d ₆) δ 12.82 (s, 1H), 3.19 (d, J = 1.9 Hz, 1H), 3.16-3.08 (m, 1H), 1.30 (d, J = 5.1 Hz, 3H)。

examples 77-254 describe the synthesis of representative compounds of formula I disclosed herein.

EXAMPLE 77 Compound 1 (2- (amino (piperidin-4-yl) methyl) -4, 5-dichlorophenol trifluoroacetic acid)

Step a:

4- [ amino (4, 5-dichloro-2-methoxyphenyl) methyl ] stirring at 0 ℃ under an argon atmosphere]Piperidine-1-carboxylic acid tert-butyl ester (70 mg, 0.18)mmol) in DCM (3 mL) BBr was added dropwise₃(0.64 g, 2.58 mmol). The reaction mixture was allowed to warm to room temperature and stirred under an argon atmosphere for 2 hours. The resulting mixture was quenched with water (2 mL) at 0 ℃ and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column 19X 250 mm, 10 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 1% B to 30% B in 15 minutes; a detector: UV 254/210 nm; retention time: 12.10 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 1 (2- (amino (piperidin-4-yl) methyl) -4, 5-dichlorophenol trifluoroacetic acid) (22.5 mg, 34%) as a violet solid, C ₁₂H₁₆Cl₂N₂O [M + H]LCMS (ESI) calculated value of +: 275, 277 (3: 2), found 275, 277 (3: 2);¹H NMR (300 MHz, CD3OD) δ 7.43 (s, 1H), 7.06 (s, 1H), 4.22 (d, J = 9.6 Hz, 1H), 3.48 (d, J = 13.0 Hz, 1H), 3.33 (d, J = 13.0 Hz, 1H), 3.06-2.83 (m, 2H), 2.49-2.30 (m, 1H), 2.20-2.07 (m, 1H), 1.67-1.36 (m, 3H)； ¹⁹F NMR (282 MHz, CD3OD) δ -76.96.

EXAMPLE 78 Compound 2 (4, 5-dichloro-2- [ hydroxy (piperidin-4-yl) methyl ] phenol)

A, step a:

stirring 4, 5-dichloro-2- [ (piperidin-4-yl) carbonyl at-40 ℃ under nitrogen]To a solution of phenol (intermediate 2, example 2) (0.20 g, 0.73 mmol) in THF (10 mL) was added NaBH in portions₄(30 mg, 0.80 mmol). The reaction mixture was stirred under nitrogen at-40 ℃ for 2 hours. The reaction mixture was purified by addition of saturated NH₄Aqueous Cl (4 mL) was quenched and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase A: having a NH concentration of 10 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 20 mL/min; gradient: within 9 minutesFrom 15% B to 50% B; a detector: UV 254/210 nm; retention time: 7.30 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 2 (4, 5-dichloro-2- [ hydroxy (piperidin-4-yl) methyl ] as an off-white solid]Phenol) (22.9 mg, 12%): C₁₂H₁₅Cl₂NO₂ [M + H]LCMS (ESI) calculated for +: 276, 278 (3: 2), found 276, 278 (3: 2);¹H NMR (300 MHz, DMSO-d ₆) δ 7.28 (s, 1H), 6.85 (s, 1H), 6.35 (br, 1H), 4.53 (d, J = 5.4 Hz, 1H), 2.96-2.77 (m, 2H), 2.40-2.16 (m, 2H), 1.63-1.40 (m, 2H), 1.37-0.98 (m, 3H)。

EXAMPLE 79 Compound 3 (4, 5-dichloro-2- [ 1-hydroxy-1- (piperidin-4-yl) ethyl ] phenol)

A, step a:

to a stirred mixture of 4, 5-dichloro-2- [ (piperidin-4-yl) carbonyl at-20 ℃ under a nitrogen atmosphere]To a solution of phenol (intermediate 2, example 2) (70 mg, 0.26 mmol) in THF (5 mL) was added MeMgBr (1.3 mL, 1.30 mmol, 1M in THF) dropwise. After stirring for a further 2 hours at-20 ℃ the resulting solution is taken up in saturated NH₄Aqueous Cl (20 mL) was quenched and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: x Bridge C18, OBD, 100A, 10 μm, 19 mm × 250 mm; mobile phase A: having a NH concentration of 10 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 15% B to 50% B in 9 minutes; a detector: UV 254/210 nm; retention time: 8.69 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 3 (4, 5-dichloro-2- [ 1-hydroxy-1- (piperidin-4-yl) ethyl) as an off-white solid]Phenol) (20 mg, 26%): C₁₃H₁₇Cl₂NO₂ [M + H]⁺Calculated lcms (esi): 290, 292 (3: 2), found 290, 292 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 6.74 (s, 1H), 3.30-3.18 (m, 2H), 2.82-2.70 (m, 2H), 2.06 (t, J =12.2 Hz, 1H), 1.82-1,68 (m, 2H), 1.54-1.47 (m, 5H)。

example 80 Compound 4 (1- (4- ((4, 5-dichloro-2-hydroxyphenyl) (hydroxy) methyl) piperidin-1-yl) ethanone)

Step a:

to a stirred solution of 1- (4- (4, 5-dichloro-2-hydroxybenzoyl) piperidin-1-yl) ethanone (intermediate 1, example 1) (0.20 g, 0.63 mmol) in THF (10 mL) at-40 deg.C under a nitrogen atmosphere was added NaBH ₄(26 mg, 0.69 mmol). After stirring for a further 2 hours at-40 ℃ under nitrogen, the reaction mixture was taken up with saturated NH₄Aqueous Cl (40 mL) was quenched and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase A: having a NH concentration of 10 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 10% B to 60% B in 8 minutes; a detector: UV 254/210 nm; retention time: 6.33 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 4 (1- (4- ((4, 5-dichloro-2-hydroxyphenyl) (hydroxy) methyl) piperidin-1-yl) ethanone) (39.4 mg, 26%) as an off-white solid C₁₄H₁₇Cl₂NO₃ [M + H]⁺Calculated lcms (esi): 318, 320 (3: 2), found 318, 320 (3: 2);¹H NMR (300 MHz, DMSO-d ₆) δ 7.45 (br, 1H), 7.34 (s, 1H), 6.90 (s, 1H), 4.60 (d, J = 5.4 Hz, 1H), 4.32 (d, J = 12.8 Hz, 1H), 3.74 (d, J = 13.4 Hz, 1H), 2.94-2.73 (m, 1H), 2.42-2.20 (m, 1H), 1.91 (s, 3H), 1.79-1.61 (m, 1H), 1.51 (d, J = 13.5 Hz, 1H), 1.40-0.98 (m, 3H)。

EXAMPLE 81 Compound 5 (4, 5-dichloro-2- [ 2-hydroxy-1- (piperidin-4-yl) ethyl ] phenol)

Step a:

to 4- [1- (4, 5-dichloro-2-methoxyphenyl) vinyl at room temperature]Piperidine-1-carboxylic acid tert-butyl ester (intermediate 17, example 17) (2.00 g, 5.18 mmol) in THF (16 mL) was added BH dropwise ₃(0.9 mL, 1M THF solution). After stirring at room temperature for 5 hours, NaOH (0.52 g, 12.94 mmol) and H were added at room temperature₂O₂(1.5 mL, 30% aqueous). The reaction solution was stirred at room temperature for 16 hours. The resulting solution was saturated with Na at room temperature₂SO₃Aqueous solution (100 mL) was quenched and extracted with EA (3X 300 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography, and purifying with CH₂Cl₂MeOH (25/1) to give 4- [1- (4, 5-dichloro-2-methoxyphenyl) -2-hydroxyethyl as an off-white solid]Piperidine-1-carboxylic acid tert-butyl ester (1.80 g, 86%): C₁₉H₂₇Cl₂NO₄ [M + H]⁺Calculated lcms (esi): 404, 406 (3: 2), measured values 404, 406 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.34 (s, 1H), 7.10 (s, 1H), 4.08 (d, J = 12.9 Hz, 1H), 3.95 (d, J = 13.5 Hz, 1H), 3.85-3.70 (m, 4H), 3.30-3.20 (m, 1H), 3.12-2.96 (m, 1H), 2.89-2.55 (m, 2H), 2.01-1.76 (m, 2H), 1.42 (s, 9H), 1.41-1.20 (m, 2H), 1.07 -0.92 (m, 1H)。

step b:

to 4- [1- (4, 5-dichloro-2-methoxyphenyl) -2-hydroxyethyl at room temperature]To a solution of tert-butyl piperidine-1-carboxylate (0.20 g, 0.51 mmol) in DCM (2 mL) was added BBr₃(0.64 g, 2.56 mmol). The reaction mixture was stirred at room temperature for 4 hours. The resulting mixture was quenched with water (10 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column, 100A, 10 μm, 19 mm × 250 mm; mobile phase A: having a NH concentration of 20 mmol/L ₄HCO₃Of water, flowPhase B: ACN; flow rate: 20 mL/min; gradient: from 30% B to 70% B in 9 minutes; a detector: UV 254/210 nm; retention time: 8.15 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 5 (4, 5-dichloro-2- [ 2-hydroxy-1- (piperidin-4-yl) ethyl) as a brown solid]Phenol) (50 mg, 29%): C₁₃H₁₇Cl₂NO₂ [M + H]⁺Calculated lcms (esi): 290, 292 (3: 2), found 290, 292 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.20 (s, 1H), 6.80 (s, 1H), 3.90-3.70 (m, 2H), 3.30-3.00 (m, 2H), 2.90-2.58 (m, 3H), 2.10-2.00 (m, 2H), 1.55-1.12 (m, 3H)。

example 82 Compound 6 (, (S) -4, 5-dichloro-2- (hydroxy (piperidin-4-yl) methyl) phenol) and compound 7 (((piperidine-4-yl) methyl)R) -4, 5-dichloro-2- (hydroxy (piperidin-4-yl) methyl) phenol)

Step a:

isolation of 4, 5-dichloro-2- [ hydroxy (piperidin-4-yl) methyl ] by preparation of SFC]Phenol (compound 2, example 78) (70 mg) column: phenomenex Lux 5 μm, Cellulose-4, AXIA Packed, 12X 25 cm, 5 μm; mobile phase A: CO 2₂(70%), mobile phase B: MeOH (30%); flow rate: 40 mL/min; a detector: UV 220 nm; retention time: RT (reverse transcription)₁5.25 minutes; RT (reverse transcription)₂5.93 minutes.

The faster eluting enantiomer, compound 6, (compound 6), (an (b), (c), was isolated as an off white solid over 5.25 minutesS) -4, 5-dichloro-2- (hydroxy (piperidin-4-yl) methyl) phenol) (15.3 mg, 22%): C ₁₂H₁₅Cl₂NO₂ [M + H]⁺Lcms (esi) calculated value of (a): 276, 278 (3: 2), found 276, 278 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.24 (s, 1H), 6.79 (s, 1H), 4.66 (d, J = 6.0 Hz, 1H), 3.24-3.08 (m, 2H), 2.67 (td, J = 12.5, 2.9 Hz, 2H), 1.92-1.73 (m, 2H), 1.56-1.34 (m, 3H)。

at 5.93The slower eluting enantiomer, Compound 7, (b), (c) was isolated as an off-white solid over a period of minutesR) -4, 5-dichloro-2- (hydroxy (piperidin-4-yl) methyl) phenol) (8.1 mg, 12%): C₁₂H₁₅Cl₂NO₂ [M + H]⁺Lcms (esi) calculated value of (a): 276, 278 (3: 2), found 276, 278 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.24 (s, 1H), 6.79 (s, 1H), 4.66 (d, J = 6.0 Hz, 1H), 3.24-3.08 (m, 2H), 2.67 (td, J = 12.5, 2.9 Hz, 2H), 1.92-1.73 (m, 2H), 1.56-1.34 (m, 3H)。

EXAMPLE 83 Compound 8 (2- [ 2-amino-1- (piperidin-4-yl) ethyl ] -4, 5-dichlorophenol)

Step a:

to 4- [1- (4, 5-dichloro-2-methoxyphenyl) -2-hydroxyethyl at room temperature]Piperidine-1-carboxylic acid tert-butyl ester (step a, example 81) (0.10 g, 0.25 mmol) and Et₃To a solution of N (50 mg, 0.50 mmol) in DCM (2 mL) was added methanesulfonyl chloride (34 mg, 0.30 mmol). The reaction solution was stirred at room temperature for 1 hour. The resulting mixture was quenched with water (30 mL) and extracted with EA (2X 30 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give crude 4- [1- (4, 5-dichloro-2-methoxyphenyl) -2- (methylsulfonyloxy) ethyl]Piperidin-1-carboxylic acid propan-2-yl ester. The crude product was used without further purification in the subsequent step: c₂₀H₂₉Cl₂NO₆S [M + H]⁺Calculated lcms (esi): 482, 484 (3: 2), found 482, 484 (3: 2).

Step b:

to 4- [1- (4, 5-dichloro-2-methoxyphenyl) -2- (methylsulfonyloxy) ethyl]To a solution of tert-butyl piperidine-1-carboxylate (crude) in DMF (5 mL) was added sodium azide (32 mg, 0.50 mmol). The reaction mixture was warmed to 80 ℃ and stirred for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water (30 mL) and extracted with EA (3 a)30 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated to one-quarter volume. Subjecting crude 4- [ 2-azido-1- (4, 5-dichloro-2-methoxyphenyl) ethyl]Piperidine-1-carboxylic acid tert-butyl ester was used in the next step without further purification C₁₉H₂₆Cl₂N₄O₃ [M + H]⁺Calculated lcms (esi): 429, 431 (3: 2), found 429, 431 (3: 2).

Step c:

to 4- [ 2-azido-1- (4, 5-dichloro-2-methoxyphenyl) ethyl at room temperature]To a solution of tert-butyl piperidine-1-carboxylate (crude) in THF (3 mL) was added PPh₃(0.23 g, 0.87 mmol) and NH₃·H₂O (1 mL, 28% aqueous solution). The reaction solution was stirred at room temperature for 2 hours. The resulting solution was diluted with water (30 mL) and extracted with EA (3X 100 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with DCM/MeOH (15/1) to give 4- [ 2-amino-1- (4, 5-dichloro-2-methoxyphenyl) ethyl as a yellow oil ]Piperidine-1-carboxylic acid tert-butyl ester (80 mg, 34.06% in total of three steps): C₁₉H₂8Cl₂N₂O₃ [M + H]⁺Lcms (esi) calculated value of (a): 403, 405 (3: 2), found 403, 405 (3: 2);¹H NMR (300 MHz, DMSO- d ₆) δ 7.37 (s, 1H), 7.22 (s, 1H), 4.13-3.99 (m, 1H), 3.96-3.81 (m, 2H), 3.76 (s, 3H), 3.17-3.12 (s, 2H), 2.96-2.78 (d, J =3.8 Hz, 2H), 2.73-2.56 (m, 2H), 1.81-1.70 (d, J = 11.5 Hz, 2H), 1.37 (s, 9H), 1.26-1.20 (m, 1H), 1.08-0.79 (m, 2H)。

step d:

to 4- [ 2-amino-1- (4, 5-dichloro-2-methoxyphenyl) ethyl at room temperature]To a solution of piperidine-1-carboxylic acid tert-butyl ester (80 mg, 0.20 mmol) in DCM (2 mL) was added BBr₃(0.40 g, 1.59 mmol). After stirring at room temperature for 2 hours, the reaction mixture was quenched with water (20 mL) at room temperature and concentrated under reduced pressure. The residue was subjected to preparative HPLC under the following conditionsPurification is as follows: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 m; mobile phase A: having a NH concentration of 20 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 30% B to 75% B in 9 minutes; a detector: UV 254/210 nm; retention time: 8.40 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 8 (2- [ 2-amino-1- (piperidin-4-yl) ethyl) as an off-white solid]-4, 5-dichlorophenol) (25 mg, 43%): C₁₃H₁₈Cl₂N₂O [M + H]⁺Calculated lcms (esi): 289, 291 (3: 2), found 289, 291 (3: 2);¹H NMR (300 MHz, DMSO-d ₆) δ 7.33 (s, 1H), 7.03 (s, 1H), 3.61-3.35 (m, 3H), 3.20-2.81 (m, 4H), 2.23-2.00 (m, 2H), 1.62-1.20 (m, 3H)。

example 84 Compound 9 (1- (4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) ethanone)

A, step a:

1- [4- [ amino (4, 5-dichloro-2-methoxyphenyl) methyl ] at 0 ℃ with stirring]Piperidin-1-yl]Ethan-1-one (30 mg, 0.09 mmol) in DCM (3 mL) was added BBr dropwise₃(0.14 g, 0.54 mmol). After stirring for a further 1 h, the reaction solution is taken up with saturated NaHCO₃The aqueous solution (20 mL) was quenched at 0 ℃ and extracted with EA (3X 40 mL). The combined organic layers were washed with brine (3X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase A: water with 20 mmol/L NH4HCO3, mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 28% B to 43% B in 9 minutes; a detector: UV 254/210 nm; retention time: 7.88 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 9 (1- (4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) ethanone) (4.5 mg, 18%): C₁₄H₁₈Cl₂N₂O₂ [M + H]LCMS (ESI) calculated for +: 317, 319 (3: 2), found 317, 319 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.22 (d, J = 2.7 Hz, 1H), 6.86 (d, J = 1.8 Hz, 1H), 4.60-4.40 (m, 1H), 4.07-3.82 (m, 2H), 3.15-2.92 (m, 1H), 2.61-2.39 (m, 1H), 2.09 (d, J = 7.0 Hz, 3H), 2.09-1.88 (m, 2H), 1.49-1.38 (m, 1H), 1.25-1.04 (m, 2H)。

example 85 Compound 10 (N-[(S) - (4, 5-dichloro-2-hydroxyphenyl) (piperidin-4-yl) methyl]Acetamide and Compound 17 ( N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) (piperidin-4-yl) methyl]Acetamide)

Step a:

separated by preparing SFC under the following conditionsN- [ (4, 5-dichloro-2-hydroxyphenyl) (piperidin-4-yl) methyl]Acetamide (47 mg, 0.15 mmol), column: phenomenex Lux, Cellulose-4A, AXIA packet, 2X 25 cm, 5 μm; mobile phase A: CO 2₂70%, mobile phase B: 30 percent of MeOH; flow rate: 40 mL/min; a detector: UV is 220 nm; retention time: RT (reverse transcription)₁5.25 minutes; RT (reverse transcription)₂5.93 minutes.

The faster eluting enantiomer was obtained as compound 17 (a), (b), (c), (d) and d) as an off-white solid over 5.25 minutesN-[(R) - (4, 5-dichloro-2-hydroxyphenyl) (piperidin-4-yl) methyl]Acetamide) (4.7 mg, 10%): C₁₄H₁₈Cl₂N₂O₂[M + H]⁺Calculated lcms (esi): 317, 319 (3: 2), found 317, 319 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.26 (d, J = 2.1 Hz, 1H), 6.89 (d, J = 1.5 Hz, 1H), 4.96-4.93 (m, 1H), 3.19 (dd, J = 36.1, 12.3 Hz, 2H), 2.69 (dt, J = 23.9, 12.4 Hz, 2H), 2.06 (d, J = 10.2 Hz, 1H), 1.99 (s, 3H), 1.94 (d, J = 14.0 Hz, 1H), 1.46 (d, J = 13.5 Hz, 1H), 1.42-1.24 (m, 2H)。

the slower eluting enantiomer was obtained as compound 10 (R) as an off-white solid at 5.93 minutesN-[(S) - (4, 5-dichloro-2-hydroxyphenyl) (piperidin-4-yl) methyl]Acetamide) (4.8 mg, 10%): C₁₄H₁₈Cl₂N₂O₂[M + H]⁺Calculated lcms (esi): 317, 319 (3: 2), found 317, 319 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 6.87 (s, 1H), 4.98-4.92 (m, 1H), 3.19 (d, J = 12.7 Hz, 1H), 3.10 (d, J = 12.7 Hz, 1H), 2.71-2.55 (m, 2H), 2.09-2.00 (m, 1H), 1.99 (s, 3H), 1.90 (d, J = 13.8 Hz, 1H), 1.43 (d, J = 13.5 Hz, 1H), 1.38-1.23 (m, 2H)。

EXAMPLE 86 Compound 11 (N- [ (4, 5-dichloro-2-hydroxyphenyl) (piperidin-4-yl) methyl ] acetamide)

Step a:

to 4- [ bromo (4, 5-dichloro-2-methoxyphenyl) methyl at room temperature ]To a solution of piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 2.21 mmol) in DMF (8 mL) was added NaN₃(0.43 g, 6.62 mmol). The resulting mixture was stirred at 100 ℃ for 16 hours. The mixture was cooled to room temperature. The reaction was diluted with water (30 mL) at room temperature. The resulting mixture was extracted with EA (4X 30 mL). The combined organic layers were washed with brine (6X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated to one-fourth volume under reduced pressure to give crude tert-butyl 4- (azido (4, 5-dichloro-2-methoxyphenyl) methyl) piperidine-1-carboxylate, which was used in the next step without further purification: c₁₈H₂₄Cl₂N₄O₃ [M + H]⁺Calculated lcms (esi): 415, 417 (3: 2), found 415, 417 (3: 2).

Step b:

to a stirred 4- [ azido (4, 5-dichloro-2-methoxyphenyl) methyl group at room temperature]Piperidine-1-carboxylic acid tert-butyl ester (crude) inTHF (8 mL) and NH₃·H₂To a solution in O (3 mL, 38% aqueous solution) was added PPh₃(1.14 g, 4.33 mmol). The resulting mixture was stirred at room temperature for 16 hours, then a solution of LiOH (0.10 g, 4.33 mmol) in water (4 mL) was added with stirring at 50 ℃ over 3 hours. The reaction was diluted with water (30 mL). The resulting mixture was extracted with EA (3X 20 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 28% aqueous ACN (plus 0.05% TFA) to give 4- [ amino (4, 5-dichloro-2-methoxyphenyl) methyl ] as a yellow oil]Piperidine-1-carboxylic acid tert-butyl ester (0.60 g, 70% of two stages in total): C₁₈H₂₆Cl₂N₂O₃ [M + H]LCMS (ESI) calculated for +: 389, 391 (3: 2), found 389, 391 (3: 2).

Step c:

to a stirred 4- [ amino (4, 5-dichloro-2-methoxyphenyl) methyl group at room temperature]To a solution of tert-butyl piperidine-1-carboxylate (0.30 g, 0.77 mmol) in DCM (3 mL) was added acetoacetate (87 mg, 0.85 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction was diluted with water (20 mL). The resulting mixture was extracted with DCM (3X 20 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 4- [ (4, 5-dichloro-2-methoxyphenyl) (acetamido) methyl group as a yellow oil]Tert-butyl piperidine-1-carboxylate (0.16 g, crude), which was used in the next step without further purification: c₂₀H₂₈Cl₂N₂O₄ [M + H]⁺Calculated lcms (esi): 431, 433 (3: 2), found 431, 433 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.38 (s, 1H), 7.16 (s, 1H), 5.04 (d, J = 8.9 Hz, 1H), 4.06 (dd, J = 36.3, 13.8 Hz, 2H), 3.89 (s, 3H), 2.80-2.58 (m, 2H), 1.99 (s, 3H), 1.85 (dd, J =51.0, 11.9 Hz, 2H), 1.46 (s, 9H), 1.36-1.09 (m, 3H)。

step d:

to a stirred mixture of 4- [ (4, 5-dichloro-2-methoxyphenyl) (acetamido) methyl]To a solution of tert-butyl piperidine-1-carboxylate (0.16 g, 0.37 mmol) in DCM (3 mL) was added BBr₃(0.74 g, 2.97 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (1 mL) at 0 ℃. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase A: has 20 mmoL/L NH₄HCO₃Water, mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 40% B to 90% B in 9 minutes; a detector: UV 254/210 nm; retention time: 8.71 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure, and the compound 11 (N- [ (4, 5-dichloro-2-hydroxyphenyl) (piperidin-4-yl) methyl) was obtained as an off-white solid]Acetamide) (47.7 mg, 20% of two steps in total): C₁₄H₁₈Cl₂N₂O₂ [M + H]⁺Calculated lcms (esi): 317, 319 (3: 2), found 317, 319 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.38 (s, 1H), 6.97 (s, 1H), 5.06 (d, J = 9.4 Hz, 1H), 3.45 (d, J = 12.9 Hz, 1H), 3.39-3.35 (m, 1H), 3.02-2.85 (m, 2H), 2.22-2.06 (m, 2H), 2.00 (s, 3H), 1.66-1.29 (m, 3H)。

example 87 Compound 12 (N- ((4, 5-dichloro-2-hydroxyphenyl) (piperidin-4-yl) methyl) methanesulfonamide)

Compound 12

Step a:

to a stirred 4- [ amino (4, 5-dichloro-2-methoxyphenyl) methyl group at room temperature]Piperidine-1-carboxylic acid tert-butyl ester (0.30 g, 0.77 mmol) and Et ₃To a solution of N (0.16 g, 1.54 mmol) in DCM (3 mL) was added methanesulfonyl chloride (0.11 g, 0.92 mmol) dropwise. After stirring at room temperature for an additional 1.5 h, the resulting mixture was quenched with water (20 mL) at room temperature and extracted with EA (3X 20 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. For treatingAfter filtration, the filtrate was concentrated under reduced pressure. The residue was used without further purification in the next step: c₁₉H₂₈Cl₂N₂O₅S [M + H]⁺Calculated lcms (esi): 467, 469 (3: 2), found 467, 469 (3: 2).

Step b:

to a stirred mixture of 4- [ (4, 5-dichloro-2-methoxyphenyl) (methanesulfonamido) methyl at 0 ℃ under a nitrogen atmosphere]Piperidine-1-carboxylic acid tert-butyl ester (crude) solution in DCM (5 mL) was added BBr dropwise₃(0.51 g, 2.05 mmol). The reaction mixture was allowed to warm to room temperature and stirred under nitrogen for 2 hours. The resulting mixture was washed with saturated NaHCO at 0 deg.C₃Aqueous solution (5 mL) was quenched. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase A: having a NH concentration of 20 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 30% B to 85% B in 9 minutes; a detector: UV 254/210 nm; retention time: 7.84 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 12 (a) as an off-white solid N- ((4, 5-dichloro-2-hydroxyphenyl) (piperidin-4-yl) methyl) methanesulfonamide) (32.9 mg, 12% of two steps in total): C₁₃H₁₈Cl₂N₂O₃S [M + H]⁺Calculated lcms (esi): 353, 357 (3: 2), found 353, 357 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.18 (s, 1H), 6.79 (s, 1H), 4.25 (d, J =8.9 Hz, 1H), 3.24-3.06 (m, 2H), 2.78-2.60 (m, 2H), 2.61 (s, 3H), 2.18-2.07 (m, 1H), 1.99-1.86 (m, 1H), 1.47-1.25 (m, 3H)。

EXAMPLE 88 Compound 13 (4, 5-dichloro-2- [ piperidin-4-yl (1H-pyrazol-1-yl) methyl ] phenol)

Step a:

to a stirred 4- [ bromo (4, 5-dichloro-2-methoxyphenyl) methyl group at room temperature]Piperidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.44 mmol) and K₂CO₃(0.12 g, 0.88 mmol) to a mixture in DMF (3 mL) was added 1H-pyrazole (60 mg, 0.88 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction was diluted with water (20 mL). The resulting mixture was extracted with EA (3X 20 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with PE/EA (1/1) to give 4- [ (4, 5-dichloro-2-methoxyphenyl) (1H-pyrazol-1-yl) methyl group as a pale yellow oil]Piperidine-1-carboxylic acid tert-butyl ester (40 mg, 21%): C₂₁H₂₇Cl₂N₃O₃ [M + H]⁺Calculated lcms (esi): 440, 442 (3: 2), found 440, 442 (3: 2).

Step b:

to a stirred mixture of 4- [ (4, 5-dichloro-2-methoxyphenyl) (1H-pyrazol-1-yl) methyl group at room temperature ]To a solution of piperidine-1-carboxylic acid tert-butyl ester (40 mg, 0.09 mmol) in DCM (1 mL) was added BBr₃(0.18 g, 0.73 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (1 mL) at 0 ℃. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase A: has 20 mmoL/L NH₄HCO₃Water, mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 20% B to 80% B in 9 minutes; a detector: UV 254/220 nm; retention time: 8.15 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 13 (4, 5-dichloro-2- [ piperidin-4-yl (1H-pyrazol-1-yl) methyl ] as an off-white solid]Phenol) (5.5 mg, 23%): C₁₅H₁₇Cl₂N₃O [M + H]⁺Calculated lcms (esi): 326, 328 (3: 2), found 326, 328 (3: 2);¹H NMR (300 MHz, CD3OD) δ 7.75 (dd, J = 2.4, 0.7 Hz, 1H), 7.63-7.51 (m, 2H), 6.90 (s, 1H), 6.27 (t, J = 2.2 Hz, 1H), 5.45 (d, J = 11.0 Hz, 1H), 3.16-3.04 (m, 2H), 2.74-2.57 (m, 2H), 1.54-1.42 (m, 1H), 1.40-1.17 (m, 4H)。

example 89 Compound 14: (N- [ (4, 5-dichloro-2-hydroxyphenyl) (1-methylpiperidin-4-yl) methyl]-2,2, 2-trifluoroacetamide)

Step a:

4- [ amino (4, 5-dichloro-2-methoxyphenyl) methyl radical stirred at 0 DEG C]Piperidine-1-carboxylic acid tert-butyl ester (0.30 g, 0.77 mmol) and Et₃To a solution of N (0.16 g, 1.54 mmol) in DCM (5 mL) was added TFAA (0.19 g, 0.92 mmol). After stirring at room temperature for an additional 4 hours, the reaction solution was quenched with water (50 mL) and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used without further purification in the subsequent step: c₂₀H₂₅Cl₂F₃N₂O₄ [M + H]⁺Lcms (esi) calculated value of (a): 485, 487 (3: 2), measured value 485, 487 (3: 2).

Step b:

4- [ (4, 5-dichloro-2-methoxyphenyl) (trifluoroacetamido) methyl group stirred at 0 DEG C]To a solution of piperidine-1-carboxylic acid tert-butyl ester (crude) in DCM (2 mL) was added TFA (2 mL). The reaction solution was allowed to warm to room temperature and stirred for 3 hours. The resulting solution was concentrated under reduced pressure. The crude product (0.35 g as TFA salt) was used directly in the next step without further purification C₁₅H₁₇Cl₂F₃N₂O₂ [M + H]⁺Calculated lcms (esi): 385, 387 (3: 2), found 385, 387 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.46 (s, 1H), 7.18 (s, 1H), 5.04 (d, J = 10.2 Hz, 1H), 3.88 (s, 3H), 3.11 (d, J = 12.7 Hz, 1H), 2.98 (d, J = 12.7 Hz, 1H), 2.66-2.42 (m, 2H), 2.06-1.86 (m, 2H), 1.38-1.11 (m, 3H)。

step c:

stirred under argon at 0 deg.CN- [ (4, 5-dichloro-2-methoxy)Phenylphenyl) (piperidin-4-yl) methyl]To a solution of-2, 2, 2-trifluoroacetamide (0.35 g, 0.91 mmol) and formaldehyde (33 mg, 1.09 mmol) in MeOH (10 mL) was added NaBH (OAc) in portions₃(0.58 g, 2.73 mmol). The reaction mixture was allowed to warm to room temperature and stirred for an additional 4 hours. The resulting mixture was washed with saturated NH₄Aqueous Cl (40 mL) was quenched and extracted with EA (3X 40 mL). The combined organic layers were washed with brine (2X 30 mL) and dried over anhydrous Na ₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with DCM/MeOH (6/1) to give a yellow oilN- ((4, 5-dichloro-2-methoxyphenyl) (1-methylpiperidin-4-yl) methyl) -2,2, 2-trifluoroacetamide (0.22 g, 70% of three stages in total): C₁₆H₁₉Cl₂F₃N₂O₂ [M + H]⁺Lcms (esi) calculated value of (a): 399, 401 (3: 2), found 399, 401 (3: 2).

Step d:

stirred in the downward direction at 0 deg.CN- [ (4, 5-dichloro-2-methoxyphenyl) (1-methylpiperidin-4-yl) methyl]BBr was added dropwise to a solution of (0.22 g, 0.55 mmol) of (E) -2,2, 2-trifluoroacetamide in DCM (5 mL)₃(0.83 g, 3.31 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was saturated with NH at 0 deg.C₄Aqueous Cl (5 mL) was quenched. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 22% aqueous ACN (plus 0.05% TFA) to afford compound 14 (b) as an off-white solidN- [ (4, 5-dichloro-2-hydroxyphenyl) (1-methylpiperidin-4-yl) methyl]-2,2, 2-trifluoroacetamide) (0.14 g, 65%): C₁₅H₁₇Cl₂F₃N₂O₂ [M + H]⁺Calculated lcms (esi): 385, 387 (3: 2), found 385, 387 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.34 (s, 1H), 6.92 (s, 1H), 4.98 (d, J = 9.9 Hz, 1H), 2.98 (d, J = 11.8 Hz, 1H), 2.89 (d, J = 11.7 Hz, 1H), 2.31 (s, 3H), 2.18-1.84 (m, 4H), 1.51-1.23 (m, 3H)； ¹⁹F NMR (282 MHz, CD₃OD) δ -77.04.

example 90. Compound 15 (, (S)-2-(Amino (piperidin-4-yl) methyl) -4, 5-dichlorophenol trifluoroacetic acid and compound 16 (((piperidine-4-yl) methyl) R) -2- (amino (piperidin-4-yl) methyl) -4, 5-dichlorophenol trifluoroacetic acid)

A, step a:

reacting 2- [ amino (piperidin-4-yl) methyl]-4, 5-dichlorophenol trifluoroacetic acid (0.30 g) is purified by preparative chiral HPLC on a column: CHIRALPAK IG, 20X 250 mm, 5 μm; a mobile phase A: hexane (0.2% IPA), mobile phase B: EtOH; flow rate: 20 mL/min; gradient: 20% B in 13 min; a detector: UV 220/254 nm; retention time: RT (reverse transcription)₁8.568 min, RT₂10.754 minutes.

The faster eluting enantiomer was obtained as compound 16 (, (r) as an off-white solid at 8.568 minutesR) -2- (amino (piperidin-4-yl) methyl) -4, 5-dichlorophenol trifluoroacetic acid) (51 mg, 17%) C₁₂H₁₆Cl₂N₂O [M + H]⁺Calculated lcms (esi): 275, 275 (3: 2), found 275, 275 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.25 (s, 1H), 6.88 (s, 1H), 3.93 (d, J = 7.7 Hz, 1H), 3.34 (d, J =12.8 Hz, 1H), 3.23 (d, J = 12.8 Hz, 1H), 2.91-2.69 (m, 2H), 2.20-1.89 (m, 2H), 1.63-1.45 (m, 1H), 1.51-1.25 (m, 2H)； ¹⁹F NMR (282 MHz, CD₃OD) δ -76.92.

the slower eluting enantiomer was obtained as compound 15 (, (r) in the form of a pale yellow solid at 10.754 minS) -2- (amino (piperidin-4-yl) methyl) -4, 5-dichlorophenol trifluoroacetic acid) (37.2 mg, 12%): C₁₂H₁₆Cl₂N₂O [M + H]⁺Calculated lcms (esi): 275, 275 (3: 2), found 275, 275 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.19 (s, 1H), 6.84 (s, 1H), 3.88 (d, J = 7.7 Hz, 1H), 3.21 (d, J = 12.6 Hz, 1H), 3.10 (d, J = 12.6 Hz, 1H), 2.80-2.56 (m, 2H), 2.04-1.86 (m, 2H), 1.57-1.41 (m, 1H), 1.40-1.19 (m, 2H)； ¹⁹F NMR (282 MHz, CD₃OD) δ -76.92.

EXAMPLE 91 Compound 18 (2- (4, 5-dichloro-2-hydroxyphenyl) -2- (piperidin-4-yl) acetamide)

Step a:

to a stirred 4- [ bromo (4, 5-dichloro-2-methoxyphenyl) methyl group at room temperature ]To a solution of piperidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.44 mmol) in DMSO (3 mL) was added KCN (0.14 g, 2.21 mmol). The mixture was stirred at 40 ℃ for 16 hours. The reaction was quenched with saturated FeSO at room temperature₄Aqueous solution (5 mL) was quenched. The resulting mixture was extracted with EA (4X 20 mL). The combined organic layers were washed with brine (4X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with PE/EA (9/1) to give 4- [ cyano (4, 5-dichloro-2-methoxyphenyl) methyl ester as a yellow oil]Piperidine-1-carboxylic acid tert-butyl ester (60 mg, 34%): C₁₉H₂₄Cl₂N₂O₃ [M + H - 15]⁺Calculated lcms (esi): 399, 401 (3: 2), measured value 399, 401 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.44 (s, 1H), 7.22 (s, 1H), 4.20-3.99 (m, 3H), 3.86 (s, 3H), 2.80-2.56 (m, 2H), 1.77 (d, J = 13.3 Hz, 1H), 1.53-1.44 (m, 1H), 1.42 (s, 9H), 1.32-1.16 (m, 3H)。

step b:

to a stirred 4- [ cyano (4, 5-dichloro-2-methoxyphenyl) methyl group at room temperature]Piperidine-1-carboxylic acid tert-butyl ester (60 mg, 0.15 mmol) and KOH (84 mg, 1.50 mmol) in a mixture of MeOH (1 mL) and water (1 mL) was added H dropwise₂O₂(51.1 mg, 1.50 mmol). The mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with PE/EA (2/1) to give 4- [ carbamoyl (4, 5-dichloro-2-methoxyphenyl) methyl group as an off-white solid ]Piperidine-1-carboxylic acid tert-butyl ester (40 mg, 64%): C₁₉H₂₆Cl₂N₂O₄ [M + H]⁺Lcms (esi) calculated value of (a): 417, 419 (3: 2), found 417, 419 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.62 (s, 1H), 7.11 (s, 1H), 4.08-3.99 (m, 2H), 3.92 (d, J = 13.4 Hz, 1H), 3.83 (s, 3H), 2.87-2.54 (m, 2H), 2.13-2.00 (m, 1H), 1.81 (d, J = 13.1 Hz, 1H), 1.41 (s, 9H), 1.3-1.15 (m, 3H)。

step c:

to a stirred 4- [ carbamoyl (4, 5-dichloro-2-methoxyphenyl) methyl group at room temperature]To a solution of tert-butyl piperidine-1-carboxylate (40 mg, 0.10 mmol) in DCM (1 mL) was added BBr₃(0.14 g, 0.58 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched with water (1 mL) at 0 ℃. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase A: has 20 mmoL/L NH₄HCO₃Water, mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 15% B to 35% B in 9 minutes; a detector: UV 254/210 nm; retention time: 7.68 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure to give compound 18 (2- (4, 5-dichloro-2-hydroxyphenyl) -2- (piperidin-4-yl) acetamide) (14.7 mg, 48%) as an off-white solid as C₁₃H₁₆Cl₂N₂O₂ [M + H]⁺Calculated lcms (esi): 303, 305 (3: 2), found 303, 305 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.32 (s, 1H), 6.86 (s, 1H), 3.59 (d, J = 10.8 Hz, 1H), 3.24-2.99 (m, 2H), 2.82-2.55 (m, 2H), 2.18 (t, J = 11.3 Hz, 1H), 1.91 (t, J = 13.4 Hz, 1H), 1.46-1.04 (m, 3H)。

example 92 Compound 19 (, (S) -1- (4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) ethanone) and compound 20 ((s) R) -1- (4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) ethanone)

Step a:

1- (4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) ethanone (compound 9, example 84) (0.23 g) was purified by preparative chiral HPLC on a column: CHIRALPAK IG UL001, 20X 250 mm, 5 μm; mobile phase A: hex, mobile phase B: EtOH; flow rate: 20 mL/min; gradient: 20% B in 19 min; a detector: UV 220/254 nm; retention time: RT (reverse transcription)₁12.36 min, RT₂15.05 minutes.

The faster eluting enantiomer was obtained as compound 20 (, (r) as an off-white solid at 12.36 minutesR) -1- (4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) ethanone) (60.2 mg, 27%): C₁₄H₁₈Cl₂N₂O₂ [M + H]⁺Calculated lcms (esi): 317, 319 (3: 2), found 317, 319 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.22 (d, J = 2.7 Hz, 1H), 6.86 (d, J = 1.8 Hz, 1H), 4.55 (dd, J = 28.9, 13.2 Hz, 1H), 4.04-03.79 (m, 2H), 3.18-2.93 (m, 1H), 2.66-2.44 (m, 1H), 2.08 (J = 7.0 Hz, 3H) 5H), 2.04-1.93 (m, 2H), 1.51-1.34 (m, 1H), 1.30-1.10 (m, 2H)。

the slower eluting enantiomer was obtained as compound 19 (, (r) as an off-white solid at 15.05 minS) -1- (4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) ethanone) (70.8 mg, 30%): C₁₄H₁₈Cl₂N₂O₂ [M + H]⁺Calculated lcms (esi): 317, 319 (3: 2), found 317, 319 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.22 (d, J = 2.7 Hz, 1H), 6.86 (d, J = 1.8 Hz, 1H), 4.55 (dd, J = 28.6, 13.0 Hz, 1H), 4.07-3.82 (m, 2H), 3.15-2.92 (m, 1H), 2.63-2.44 (m, 1H), 2.06 (d, J = 7.0 Hz, 3H), 2.06-1.92 (m, 2H), 1.51-1.34 (m, 1H), 1.30-1.10 (m, 2H)。

EXAMPLE 93 Compound 21 (2- (amino (1-methylpiperidin-4-yl) methyl) -4, 5-dichlorophenol)

Step a:

at room temperature with stirringN- [ (4, 5-dichloro-2-hydroxyphenyl) (1-methylpiperidin-4-yl) methyl]-2,2, 2-trifluoroacetamide (compound 14, example 89) (0.12 g, 0.31 mmol) in MeOH (5 mL) is added dropwise a solution of NaOH (62 mg, 1.56 mmol) in water (1 mL). The reaction solution was stirred at room temperature for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase A: having a NH concentration of 20 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 17% B to 52% B in 9 minutes; a detector: UV 210 nm; retention time: 8.58 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 21 (2- (amino (1-methylpiperidin-4-yl) methyl) -4, 5-dichlorophenol) (19 mg, 21%) as an off-white solid, C₁₃H₁₈Cl₂N₂O [M + H]⁺Calculated lcms (esi): 289, 291 (3: 2), found 289, 291 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.18 (s, 1H), 6.83 (s, 1H), 3.87 (d, J = 7.9 Hz, 1H), 3.01-2.77 (m, 2H), 2.26 (s, 3H), 2.09-1.86 (m, 3H), 1.84-1.67 (m, 1H), 1.47-1.25 (m, 3H)。

example 94 Compound 22 (N- ((4, 5-dichloro-2-hydroxyphenyl) (piperidin-4-yl) methyl) -2,2, 2-trifluoroacetamide)

Step a:

stirred in the downward direction at 0 deg.CN- [ (4, 5-dichloro-2-methoxyphenyl) (piperidin-4-yl) methyl ]A solution of-2, 2, 2-trifluoroacetamide (example 89, step b) (80 mg, 0.21 mmol) in DCM (2 mL) was added dropwise tribromoborane (0.42 g, 1.66 mmol). After stirring for a further 3 hours at room temperature, the reaction mixture is left at 0 DEG CWith saturated NaHCO₃Aqueous solution (3 mL) was quenched. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase A: having a NH concentration of 20 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 18% B to 55% B in 9 minutes; a detector: UV 210 nm; retention time: 8.08 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 22 (b) as an off-white solidN- ((4, 5-dichloro-2-hydroxyphenyl) (piperidin-4-yl) methyl) -2,2, 2-trifluoroacetamide) (20 mg, 26%): C₁₄H₁₅Cl₂F₃N₂O₂ [M + H]⁺Calculated lcms (esi): 371, 373 (3: 2), found 371, 373 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.24 (d, J = 3.0 Hz, 1H), 6.86 (s, 1H), 4.86 (d, J = 9.2 Hz, 1H), 3.29-3.13 (m, 2H), 2.92-2.58 (m, 2H), 2.35-2.02 (m, 1H), 1.96-1.80 (m, 1H), 1.56-1.25 (m, 3H)； ¹⁹F NMR (282 MHz, CD₃OD) δ -77.08.

EXAMPLE 95 Compound 23 (1- (4- ((4, 5-dichloro-2-hydroxyphenyl) (pyrrolidin-1-yl) methyl) piperidin-1-yl) ethanone trifluoroacetic acid)

Step a:

to a stirred 1- [4- [ bromo (4, 5-dichloro-2-methoxyphenyl) methyl group at room temperature]Piperidin-1-yl radical]To a solution of ethan-1-one (0.40 g, 1.01 mmol) and pyrrolidine (0.72 g, 10.10 mmol) in DMSO (5 mL) was added Na ₂CO₃(0.32 g, 3.04 mmol). The resulting mixture was warmed to 50 ℃ and stirred for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 mL). The resulting mixture was extracted with EA (3X 30 mL). The combined organic layers were washed with water (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC on CH₂Cl₂The elution was carried out with/MeOH (20/1),obtaining 1- [4- [ (4, 5-dichloro-2-methoxyphenyl) (pyrrolidin-1-yl) methyl group as an off-white solid]Piperidin-1-yl radical]Ethan-1-one (0.29 g, 74%): C₁₉H₂₆Cl₂N₂O₂ [M + H]LCMS (ESI) calculated for +: 385, 387 (3: 2), found 385, 387 (3: 2).

Step b:

1- [4- [ (4, 5-dichloro-2-methoxyphenyl) (pyrrolidin-1-yl) methyl]Piperidin-1-yl radical]A solution of ethan-1-one (0.27 g, 0.70 mmol) in hydrogen iodide (4 mL) was stirred at 100 ℃ for 20 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 20% B to 50% B in 8 minutes; a detector: UV 254/210 nm; retention time: 6.12 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 23 (1- [4- [ (4, 5-dichloro-2-hydroxyphenyl) (pyrrolidin-1-yl) methyl) as a pale yellow solid ]Piperidin-1-yl]Ethanone trifluoroacetic acid) (19 mg, 7%): C₁₈H₂₄Cl₂N₂O₂ [M + H]⁺Lcms (esi) calculated value of (a): 371, 373 (3: 2), found 371, 373 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.31 (s, 1H), 7.12 (s, 1H), 4.65-4.49 (m, 1H), 4.34-4.29 (m, 1H), 4.26-3.71 (m, 2H), 3.52-3.34 (m, 2H), 3.25-2.95 (m, 2H), 2.73-2.51 (m, 2H), 2.29-1.86 (m, 9H), 1.29-0.92 (m, 2H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -76.99.

example 96 Compound 24 (, (R) -4, 5-dichloro-2- (hydroxy (1-methylpiperidin-4-yl) methyl) phenol) and compound 319 (, (S) -4, 5-dichloro-2- (hydroxy (1-methylpiperidin-4-yl) methyl) phenol)

Step a:

to a stirred 4, 5-dichloro-2- [ (piperidin-4-yl) carbonyl group at room temperature]Phenol (intermediate 2, example 2) (0.31 g,1.12 mol), AcOH (74 mg, 1.24 mol) and HCHO (41 mg, 1.35 mmol) in MeOH (5 mL) were added NaBH (OAc) portionwise₃(0.71 g, 3.37 mol). The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (30 mL) at room temperature. The resulting mixture was extracted with EA (3X 100 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column, 100A, 10 μm, 19 mm × 250 mm; mobile phase A: has 20 mmoL/L NH₄HCO₃Water, mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 16% B to 54% B in 9 minutes; a detector: UV 254/210 nm; retention time: 7.95 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure and afforded 4, 5-dichloro-2- [ hydroxy (1-methylpiperidin-4-yl) methyl as an off-white solid ]Phenol (70 mg, 21%): C₁₃H₁₇Cl₂NO₂ [M + H]⁺Lcms (esi) calculated value of (a): 290, 292 (3: 2) found: 290, 292 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.34 (s, 1H), 6.87 (s, 1H), 4.72 (d, J = 6.5 Hz, 1H), 3.00-2.83 (m, 2H), 2.27 (s, 3H), 2.11-1.93 (m, 2H), 1.93-1.81 (m, 1H), 1.71-1.55 (m, 1H), 1.55-1.37 (m, 3H)。

step b:

4, 5-dichloro-2- (hydroxy (1-methylpiperidin-4-yl) methyl) phenol (25 mg) was purified by preparative chiral HPLC on a column: column: CHIRALPAK AD-H, 2X 25 cm; mobile phase A: hexane (0.1% DEA); mobile phase B: IPA; flow rate: 20 mL/min; gradient: from 5% B to 5% B in 20 minutes; a detector: UV 220/254 nm; retention time: RT (reverse transcription)₁13.55 minutes, RT₂16.98 minutes; injection volume 0.3 mL.

The faster eluting enantiomer was obtained as compound 24 (, (r) as an off-white solid at 16.98 minR) -4, 5-dichloro-2- (hydroxy (1-methylpiperidin-4-yl) methyl) phenol) (7.7 mg, 31%): C₁₃H₁₇Cl₂NO₂ [M + H]⁺Calculated lcms (esi): 290, 292 (3: 2),found 290, 292 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.34 (s, 1H), 6.87 (s, 1H), 4.72 (d, J = 6.5 Hz, 1H), 2.93 (t, J =12.0 Hz, 2H), 2.28 (s, 3H), 2.09-1.96 (m, 2H), 1.94-1.78 (m, 1H), 1.75-1.33 (m, 4H)。

the slower eluting enantiomer was obtained as compound 319 in the form of an off-white solid at 16.98 min (, (S) -4, 5-dichloro-2- (hydroxy (1-methylpiperidin-4-yl) methyl) phenol) (8.3 mg, 33%): C₁₃H₁₇Cl₂NO₂ [M + H]⁺Calculated lcms (esi): 290, 292 (3: 2), found 290, 292 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.34 (s, 1H), 6.87 (s, 1H), 4.72 (d, J = 6.5 Hz, 1H), 2.93 (t, J = 12.0 Hz, 2H), 2.28 (s, 3H), 2.09-1.96 (m, 2H), 1.94-1.78 (m, 1H), 1.75-1.33 (m, 4H)。

EXAMPLE 97 Compound 254, 5-dichloro-2- (1-hydroxy-1- (piperidin-4-yl) ethyl) phenol isomer 1 and Compound 264, 5-dichloro-2- (1-hydroxy-1- (piperidin-4-yl) ethyl) phenol isomer 2

A, step a:

4, 5-dichloro-2- (1-hydroxy-1- (piperidin-4-yl) ethyl) phenol (20 mg, 0.07 mmol) was isolated by preparative SFC on column: phenomenex Lux Cellulose-4, AXIA Packed, 2.12X 25 cm, 5 μm; mobile phase A: CO 2₂ (70%), mobile phase B: MeOH (2 mmol NH)₃MeOH solution of) 30%; flow rate: 40 mL/min; a detector: UV 220 nm; retention time: RT (reverse transcription)₁4.9 minutes; RT (reverse transcription)₂5.8 minutes.

The faster eluting enantiomer was obtained as compound 25 (4, 5-dichloro-2- (1-hydroxy-1- (piperidin-4-yl) ethyl) phenol isomer 1) (3.7 mg, 18%) as an off-white solid at 4.9 minutes: neither as compound as a: neither as a₁₃H₁₇Cl₂NO₂ [M + 1]⁺Calculated lcms (esi): 290, 292 (3: 2), found 290, 292 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 6.74 (s, 1H), 3.30-3.18 (m, 2H), 2.82-2.70 (m, 2H), 2.06 (t, J = 12.2 Hz, 1H), 1.82-1,68 (m, 2H), 1.54-1.47 (m, 5H)。

the slower eluting enantiomer was obtained as compound 26 (4, 5-dichloro-2- (1-hydroxy-1- (piperidin-4-yl) ethyl) phenol isomer 2) (3.9 mg, 19%) as an off-white solid at 5.8 minutes C₁₃H₁₇Cl₂NO₂ [M + H]⁺Calculated lcms (esi): 290, 292 (3: 2), found 290, 292 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.16 (s, 1H), 6.74 (s, 1H), 3.30-3.18 (m, 2H), 2.82-2.70 (m, 2H), 2.06 (t, J = 12.2 Hz, 1H), 1.82-1,68 (m, 2H), 1.54-1.47 (m, 5H)。

EXAMPLE 98 Compound 27 (1- [4- [ (4, 5-dichloro-2-hydroxyphenyl) [ (pyridin-2-yl) amino ] methyl ] piperidin-1-yl ] eth-1-one trifluoroacetic acid)

Step a:

to a stirred 1- [4- [ amino (4, 5-dichloro-2-methoxyphenyl) methyl group at room temperature under argon atmosphere ]Piperidin-1-yl radical]To a mixture of ethan-1-one (0.20 g, 0.60 mmol) and 2-bromopyridine (0.14 g, 0.91 mmol) in 1, 4-dioxane (3 mL) was added xanthphos (35 mg, 0.06 mmol),t-BuONa (0.17 g, 1.81 mmol) and Pd₂(dba)₃·CHCl₃(63 mg, 0.06 mmol). The mixture was stirred at 80 ℃ for 2 hours under an argon atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (7/1) to give a yellow oilN- [ (4, 5-dichloro-2-methoxyphenyl) [1- (prop-1-en-2-yl) piperidin-4-yl)]Methyl radical]Pyridine-2-amine (56 mg, 18%): C₂₀H₂₃Cl₂N₃O₂ [M + H]⁺Calculated lcms (esi): 408, 410 (3: 2), found 408, 410 (3: 2).

Step b:

at room temperature with stirringN- [ (4, 5-dichloro-2-methoxyphenyl) (piperidin-4-yl) methyl]To a solution of pyridin-2-amine (56.00 mg, 0.15 mmol) in DCM (1 mL) was added BBr₃(0.23 g, 0.92 mmol). The reaction was stirred at room temperature for 3 hours. The reaction was quenched with water (1 mL) at 0 ℃. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 20% B to 38% B in 8 minutes; a detector: UV 254/210 nm; retention time: 7.38 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure to give compound 27 (1- [4- [ (4, 5-dichloro-2-hydroxyphenyl) [ (pyridin-2-yl) amino) as an off-white solid ]Methyl radical]Piperidin-1-yl]Ethan-1-one trifluoroacetic acid) (10 mg, 16%): C₁₉H₂₁Cl₂N₃O₂ [M + H]⁺Calculated lcms (esi): 394, 396 (3: 2), found 394, 396 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.99-7.92 (m, 1H), 7.90 (d, J = 6.4 Hz, 1H), 7.46 (d, J = 6.9 Hz, 1H), 7.10 (d, J = 9.2 Hz, 1H), 7.03 (s, 1H), 6.93 (t, J = 6.8 Hz, 1H), 4.78 (t, J = 9.1 Hz, 1H), 4.57 (dd, J = 31.7, 13.3 Hz, 1H), 3.98 (dd, J = 30.2, 13.7 Hz, 1H), 3.12 (dt, J = 25.8, 13.4 Hz, 1H), 2.63 (dt, J = 24.5, 12.4 Hz, 1H), 2.42-2.30 (m, 1H), 2.11 (d, J = 6.3 Hz, 3H), 2.08-1.97 (m, 1H), 1.55-1.18 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.02.

EXAMPLE 99 Compound 28 (1- [4- [ 2-amino-1- (4, 5-dichloro-2-hydroxyphenyl) ethyl ] piperidin-1-yl ] ethan-1-one)

Step a:

to 1- [4- [ bromo (4, 5-dichloro-2-methoxyphenyl) methyl at room temperature]Piperidin-1-yl radical]To a solution of ethan-1-one (0.50 g, 1.27 mmol) in DMSO (5 mL) was added KCN (0.25g, 3.81 mmol). The reaction mixture was warmed to 50 ℃ and stirred for 19 hours. After cooling to room temperature, the resulting mixture was quenched with saturated FeSO₄Aqueous solution (50 mL) was quenched and extracted with EA (3X 30 mL). The combined organic layers were washed with water (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE/EA (5/1) to give 2- (1-acetylpiperidin-4-yl) -2- (4, 5-dichloro-2-methoxyphenyl) acetonitrile (0.37 g, 86%) as an off-white solid C₁₆H₁₈Cl₂N₂O₂ [M + H]⁺Calculated lcms (esi): 341, 343 (3: 2), found 341, 343 (3: 2);¹H-NMR (400 MHz, DMSO-d ₆) δ 7.54 (d, J = 2.1 Hz, 1H), 7.42 (s, 1H), 4.38 (dd, J = 35.2, 13.3 Hz, 1H), 4.22 (d, J = 8.2 Hz, 1H), 3.92 (s, 3H), 3.87-3.69 (m, 1H), 3.09-2.86 (m, 1H), 2.49-2.38 (m, 1H), 2.25-2.08 (m, 1H), 1.97 (s, 3H), 1.91-1.74 (m, 1H), 1.43-1.31 (m, 1H), 1.35-1.26 (m, 1H), 1.08-0.94 (m, 1H)。

step b:

to stirred 2- (1-acetylpiperidin-4-yl) -2- (4, 5-dichloro-2-methoxyphenyl) acetonitrile (0.37 g, 1.09 mmol) and NH at room temperature under nitrogen atmosphere ₃·H₂To a solution of O (0.5 mL, 12.84 mmol, 28% aq) in MeOH (5 mL) was added Raney nickel (37 mg, 0.43 mmol). After the addition, the reaction mixture was degassed three times under hydrogen and stirred at room temperature under 1.5 atm hydrogen for 20 hours. The resulting mixture was filtered and the filter cake was washed with MeOH (3X 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC on CH₂Cl₂MeOH (15/1) gave 1- [4- [ 2-amino-1- (4, 5-dichloro-2-methoxyphenyl) ethyl as a green oil]Piperidin-1-yl radical]Ethan-1-one (0.33 g, 87%): C₁₆H₂₂Cl₂N₂O₂ [M + H]⁺Calculated lcms (esi): 345, 347 (3: 2), found 345, 347 (3: 2);¹H-NMR (300 MHz, CD₃OD) δ 7.30 (d, J = 2.1 Hz, 1H), 7.16 (s, 1H), 4.47 (dd, J = 35.2 13.3 Hz, 1H), 3.98-3.75 (m,1H), 3.85 (s, 3H), 3.13-2.88 (m, 3H), 2.68-2.41 (m, 1H), 2.06 (d, J = 10.1 Hz, 3H), 1.99-1.83 (m, 2H), 1.43-0.85 (m, 4H)。

step c:

to a stirred 1- [4- [ 2-amino-1- (4, 5-dichloro-2-methoxyphenyl) ethyl group at room temperature]Piperidin-1-yl radical]Ethan-1-one (0.16 g, 0.46 mmol) and Et₃N (70 mg, 0.70 mmol) in CH₂Cl₂To the solution in (2 mL) was added TFAA (0.11 g, 0.51 mmol). The reaction solution was stirred at room temperature for 1 hour. Concentrating the obtained solution under reduced pressure to obtain light yellow oilN- [2- (1-acetylpiperidin-4-yl) -2- (4, 5-dichloro-2-methoxyphenyl) ethyl]2,2, 2-Trifluoroacetamide (0.17 g, crude), which is used in the subsequent step without further purification C₁₈H₂₁Cl₂F₃N₂O₃[M + H]⁺Calculated lcms (esi): 441, 443 (3: 2), found 441, 443 (3: 2).

Step d:

at room temperature toN- [2- (1-acetylpiperidin-4-yl) -2- (4, 5-dichloro-2-methoxyphenyl) ethyl]To a solution of (E) -2,2, 2-trifluoroacetamide (0.17 g, crude) in DCM (5 mL) was added BBr₃(1.00 g, 3.97 mmol). After stirring at room temperature for 1 hour, the resulting solution was saturated with Na at room temperature₂CO₃Aqueous solution (20 mL) was quenched and extracted with EA (3X 20 mL). The combined organic layers were washed with water (3X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE/EA (1/3) to give N- [2- (1-acetylpiperidin-4-yl) -2- (4, 5-dichloro-2-hydroxyphenyl) ethyl as an off-white solid]-2,2, 2-trifluoroacetamide (0.14 g, 83%): C₁₇H₁₉Cl₂F₃N₂O₃ [M + H]⁺Calculated lcms (esi): 427, 429, found 427, 429;¹H NMR (400 MHz, CD₃OD) δ 7.21 (d, J = 2.5 Hz, 1H), 6.92 (s, 1H), 4.49 (dd, J = 52.9, 13.4 Hz, 1H), 3.91 (dd, J = 51.4, 13.9 Hz, 1H), 3.77-3.67 (m, 1H), 3.64-3.50 (m, 1H), 3.23-2.96 (m, 2H), 2.71-2.52 (m, 1H), 2.17-2.05 (m, 2H), 2.10 (d, J = 15.8 Hz, 3H), 1.56-1.42 (m, 1H), 1.38-1.20 (m, 1H), 1.14-0.92 (m, 1H)； ¹⁹F-NMR (376 MHz, CD₃OD) δ -77.41.

step e:

at room temperature with stirringN- [2- (1-acetylpiperidin-4-yl) -2- (4, 5-dichloro-2-hydroxyphenyl) ethyl]To a solution of-2, 2, 2-trifluoroacetamide (0.14 g, 0.33 mmol) in MeOH/water (5 mL/1 mL) was added KOH (37 mg, 0.66 mmol). The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge C18 OBD, 100 a, 10 μm, 19 mm × 250 mm; mobile phase A: having a NH concentration of 20 mmol/L ₄HCO₃Water, mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 25% B to 55% B in 8 minutes; a detector: UV 254/210 nm; retention time: 6.22 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 28 (1- [4- [ 2-amino-1- (4, 5-dichloro-2-hydroxyphenyl) ethyl) 28 as an off-white solid]Piperidin-1-yl radical]Ethan-1-one) (43 mg, 40%): C₁₅H₂₀C_l2N₂O₂ [M + H]⁺Calculated lcms (esi): 331, 333 (3: 2), found 331, 333 (3: 2);¹H NMR (400 MHz, CD₃OD) ¹H NMR (400 MHz, CD₃OD) δ 7.10 (s, 1H), 6.85 (d, J = 7.5 Hz, 1H), 4.52 (dd, J = 51.7, 12.8 Hz, 1H), 3.93 (dd, J = 48.6, 13.8 Hz, 1H), 3.28-2.99 (m, 3H), 2.71-2.49 (m, 2H), 2.27-2.17 (m, 1H), 2.08 (d, J = 13.9 Hz, 3H), 2.05-1.97 (m, 1H), 1.45-0.90 (m, 3H)。

example 100 Compound 29 (1- ((4, 5-dichloro-2-hydroxyphenyl) (piperidin-4-yl) methyl) pyrrolidin-2-one trifluoroacetic acid)

Step a:

to a stirred 4- [ amino (4, 5-dichloro-2-methoxyphenyl) methyl group at room temperature]Piperidine-1-carboxylic acid tert-butyl ester (0.25 g, 0.64 mmol) and Et₃N (97 mg, 0.96 mmol) in CH₂Cl₂(5 mL) was added dropwise 4-chlorobutyryl chloride (0.10 g, 0.71 mmol). The reaction solution was stirred at room temperature for 16 hours. The resulting solution was quenched with water (30 mL) at room temperature and extracted with EA (3X 25 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (0.35 g) was used without further purification in the subsequent step C₂₂H₃₁Cl₃N₂O₄ [M + H]⁺Calculated lcms (esi): 493, 495 (3: 2), found 493, 495 (3: 2).

Step b:

to a stirred solution of tert-butyl 4- ((4-chlorobutanamido) (4, 5-dichloro-2-methoxyphenyl) methyl) piperidine-1-carboxylate (0.35 g, crude) in DMF (5 mL) under an argon atmosphere was added NaH (0.14 g, 3.54 mmol, 60% mineral oil solution) portionwise at 0 ℃. The reaction mixture was stirred under an argon atmosphere at 50 ℃ 16. The resulting mixture was quenched with water (40 mL) at 0 ℃ and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE/EA (3/1) to give tert-butyl 4- ((4, 5-dichloro-2-methoxyphenyl) (2-oxopyrrolidin-1-yl) methyl) piperidine-1-carboxylate (0.25 g, 83%) as a pale yellow solid C₂₂H₃₀C_l2N₂O₄ [M + H]⁺Calculated lcms (esi): 457, 459 (3: 2), found 457, 459 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.57 (s, 1H), 7.21 (s, 1H), 5.16 (d, J = 11.5 Hz, 1H), 4.16-4.05 (m, 1H), 4.05-3.96 (m, 1H), 3.84 (S, 3H), 3.55-3.44 (m, 1H), 3.16-3.08 (m, 1H), 2.97-2.71 (m, 2H), 2.58-2.48 (m, 1H), 2.42-2.28 (m, 2H), 2.07-1.84 (m, 3H), 1.70-160 (m, 1H), 1.50 (s, 9H), 1.621.29 (m, 2H)。

step c:

stirring 4- [ (4, 5-dichloro-2-methoxyphenyl) (2-oxopyrrolidin-1-yl) methyl at 0 deg.C]Piperidine-1-carboxylic acid tert-butyl ester (0.25 g, 0.55 m)mol) solution in DCM (5 mL) BBr was added dropwise₃(1.10 g, 4.37 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was washed with saturated NaHCO at 0 deg.C ₃Aqueous solution (30 mL) was quenched. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 25% B to 53% B in 6.5 min; a detector: UV 254/210 nm; retention time: 4.57 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 29 (1- ((4, 5-dichloro-2-hydroxyphenyl) (piperidin-4-yl) methyl) pyrrolidin-2-one trifluoroacetic acid) (75.2 mg, 40%) as a violet solid₁₆H₂₀Cl₂N₂O₂ [M + H]⁺Calculated lcms (esi): 343, 345 (3: 2), found 343, 345 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.51 (s, 1H), 7.01 (s, 1H), 5.17 (d, J = 11.5 Hz, 1H), 3.59-3.43 (m, 2H), 3.40-3.30 (m, 1H), 3.25-3.13 (m, 1H), 3.13-2.93 (m, 2H), 2.78-2.60 (m, 1H), 2.47-2.33 (m, 2H), 2.10-1.90 (m, 3H), 1.70 (d, J = 14.5 Hz, 1H), 1.62-1.47 (m, 1H), 1.44-1.29 (m, 1H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.08.

example 101 Compound 30 (1- (hydroxy (piperidin-4-yl) methyl) naphthalen-2-ol)

Step a:

to a stirred solution of 2-methoxynaphthalene (0.38 g, 2.45 mmol) and 1-acetylpiperidine-4-carbonyl chloride (0.55 g, 2.94 mmol) in DCE (5 mL) at room temperature was added AlCl₃(0.96 g, 7.21 mmol). The resulting mixture was stirred at 50 ℃ for 6 hours under nitrogen atmosphere. The reaction was quenched with water (20 mL) at 0 ℃. The resulting mixture was extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After the filtration, the mixture is filtered out,the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EA 1/1) to give 1- [4- [ (2-methoxynaphthalen-1-yl) carbonyl ] as a pale yellow oil]Piperidin-1-yl]Ethan-1-one (0.40 g, 53%) (LCMS (ESI)) calcd for C₁₉H₂₁NO₃ [M + H]⁺312 measured value: 312;¹H NMR (400 MHz, CD₃OD) δ 8.58 (d, J = 1.8 Hz, 1H), 8.05-7.93 (m, 2H), 7.93-7.82 (m, 1H), 7.36-7.29 (m, 1H), 7.25 (dd, J= 9.0, 2.5 Hz, 1H), 4.61-4.52 (m, 1H), 4.07-3.99 (m, 1H), 3.97 (s, 3H), 3.93-3.82 (m, 1H), 3.43-3.35 (m, 1H), 2.95 (td, J = 12.7, 2.9 Hz, 1H), 2.15 (s, 3H), 2.03-1.93 (m, 2H), 1.82-1.55 (m, 2H)。

step b:

1- (4- (2-methoxy-1-naphthoyl) piperidin-1-yl) ethanone (0.15 g, 0.07 mmol) in aqueous HCl (6)N5 mL) was stirred at 100 ℃ for 4 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The resulting mixture was taken up in saturated NaHCO₃The pH was adjusted to 8 with aqueous solution and then extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure the residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD, 100A, 10 μm, 19 mm × 250 mm; mobile phase A: having a NH concentration of 20 mmol/L₄HCO₃Water of (2); mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 11% B to 50% B in 6.5 minutes; a detector: UV 254/210 nm; retention time: 5.52 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give (2-hydroxynaphthalen-1-yl) (piperidin-4-yl) methanone (35 mg, 30%) as an off-white solid C ₁₆H₁₇NO₂ [M + H]⁺Lcms (esi) calculated value of (a): 256, found 256;¹H NMR (400 MHz, CD₃OD) δ 7.83-7.73 (m, 2H), 7.64 (d, J = 8.6 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H), 7.28 (t, J = 7.5 Hz, 1H), 7.12 (d, J = 8.9 Hz, 1H), 3.22-3.10 (m, 3H), 2.75 (t, J = 12.3 Hz, 2H), 1.97 (d, J = 13.7 Hz, 2H), 1.76 (t, J = 12.9 Hz, 2H)。

step c:

to a stirred solution of (2-hydroxynaphthalen-1-yl) (piperidin-4-yl) methanone (30 mg, 0.12 mmol) in MeOH under nitrogen at room temperature was added NaBH₄(9 mg, 0.24 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The resulting mixture was quenched with water (10 mL) at room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD, 100A, 10 μm, 19 mm × 250 mm; mobile phase A: water with 20 mmol/L NH₄HCO₃(ii) a Mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 10% B to 40% B in 9 minutes; a detector: UV 254/210 nm; retention time: 6.10 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 30 (1- (hydroxy (piperidin-4-yl) methyl) naphthalen-2-ol) (7.5 mg, 25%) as an off-white solid C₁₆H₁₉NO₂ [M + H]⁺Calculated lcms (esi): 258, found 258;¹H NMR (400 MHz, CD₃OD) δ 7.94 (s, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.26 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 8.7 Hz, 1H), 5.46 (d, J = 6.5 Hz, 1H), 3.18 (d, J = 12.9 Hz, 1H), 3.07 (d, J = 12.5 Hz, 1H), 2.65-2.52 (m, 2H), 2.21-1.98 (m, 2H), 1.69-1.51 (m, 2H), 1.49-1.37 (m, 1H)。

EXAMPLE 102 Compound 31 (4, 5-dichloro-2- [ (methylamino) (piperidin-4-yl) methyl ] phenol trifluoroacetic acid)

Step a:

to a stirred 1- [4- [ (4, 5-dichloro-2-methoxyphenyl) carbonyl group at room temperature under a nitrogen atmosphere]Piperidin-1-yl radical]Ethyl-1-one (example 4, step a) (0.25 g, 0.76 mmol) in MeOH (5 mL) was added methylamine hydrochloride (0.26 g, 3.79 mmol) and NaBH ₃CN (0.14 g, 2.27 mmol). After stirring at 60 ℃ for 8 hours under nitrogen atmosphere, the reaction mixture was cooled to room temperatureAnd (4) warming. The resulting mixture was quenched with water (5 mL) at room temperature and concentrated under reduced pressure. The residue was purified by reverse phase chromatography using a column containing 20 mmol/L NH₄HCO₃Eluting with 60% aqueous ACN solution to obtain 1- [4- [ (4, 5-dichloro-2-methoxyphenyl) (methylamino) methyl ] amino]Piperidin-1-yl radical]Ethan-1-one (0.20 g, 76%): C₁₆H₂₂Cl₂N₂O₂ [M + H]⁺Calculated lcms (esi): 345, 347 (3: 2), found 345, 347 (3: 2).

Step b:

to a stirred mixture of 1- [4- [ (4, 5-dichloro-2-methoxyphenyl) (methylamino) methyl at 0 ℃ under a nitrogen atmosphere]Piperidin-1-yl radical]To a solution of ethan-1-one (0.20 g, 0.58 mmol) in DCM (2 mL) was added BBr₃(0.72 g, 2.90 mmol). The reaction mixture was allowed to warm to room temperature and stirred under nitrogen for 1 hour. The resulting mixture was quenched with water (2 mL) at room temperature and concentrated under reduced pressure to give crude 1- (4- ((4, 5-dichloro-2-hydroxyphenyl) (methylamino) methyl) piperidin-1-yl) ethanone. The crude product was used without further purification in the subsequent step: c₁₅H₂₀C_l2N₂O₂ [M + H]⁺Calculated lcms (esi): 331, 333 (3: 2), found 331, 333 (3: 2).

Step c:

1- [4- [ (4, 5-dichloro-2-hydroxyphenyl) (methylamino) methyl group]Piperidin-1-yl radical]A solution of ethan-1-one (0.18 g, 0.54 mmol) in aqueous HCl (6N, 10 mL) was stirred at 120 ℃ for 5 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: SunAire Prep C18 OBD column 19X 150 mm, 5 μm, 10 nm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 11% B to 25% B in 9 minutes; a detector: UV 254/210 nm; retention time: 7.87 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 31 (4, 5-dichloro-2- [ (methylamino) (piperidin-4-yl) methyl) as an off-white solid]Phenol trifluoroacetic acid) (25 mg, 15%): C₁₃H₁₈Cl₂N₂O [M + H]⁺Calculated lcms (esi): 289, 291 (3: 2),found 289, 291 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.48 (s, 1H), 7.13 (s, 1H), 4.27 (d, J = 8.6 Hz, 1H), 3.52 (d, J = 13.1 Hz, 1H), 3.39 (d, J = 13.1 Hz, 1H), 3.13-2.86 (m, 2H), 2.59 (s, 3H), 2.59-2.44 (m, 1H), 2.24 (d, J = 13.7 Hz, 1H), 1.76-1.33 (m, 3H)； ¹⁹F NMR (282, CD₃OD) δ -76.96.

EXAMPLE 103 Compound 32 (2- (amino (pyrrolidin-3-yl) methyl) -4, 5-dichlorophenol trifluoroacetic acid diastereomer 1) and Compound 33 (2- (amino (pyrrolidin-3-yl) methyl) -4, 5-dichlorophenol trifluoroacetic acid diastereomer 2)

Step a:

to a stirred mixture of 1-acetylpyrrolidine-3-carboxylic acid (intermediate 62, example 62) (0.49 g, 3.09 mmol) in DCM (5 mL) was added dropwise sulfuryl chloride (1.10 g, 9.28 mmol) at room temperature under nitrogen. The reaction was concentrated under reduced pressure. The residue was dissolved in DCE (6 mL) and the solution was added dropwise to 1, 2-dichloro-4-methoxybenzene (0.34 g, 1.90 mmol) and AlCl under nitrogen at-5 deg.C ₃(1.23 g, 9.26 mmol) in DCE (10 mL). The reaction mixture was stirred at 0 ℃ for 16 hours. The reaction was quenched with water (25 mL) at-5 ℃. The resulting mixture was extracted with EA (3X 30 mL). The combined organic layers were washed with aqueous HCl (1)N3X 20 mL) over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with DCM/MeOH (10/1) to give 1- [3- [ (4, 5-dichloro-2-hydroxyphenyl) carbonyl group as a pale yellow oil]Pyrrolidin-1-yl radical]Ethan-1-one (0.49 g, 45%): C₁₃H₁₃Cl₂NO₃ [M + H]⁺Calculated lcms (esi): 302, 304 (3: 2), measured 302, 304 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 8.12 (d, J = 7.4 Hz, 1H), 7.22 (d, J = 2.6 Hz, 1H), 4.42-4.17 (m, 1H), 3.93-3.70 (m, 2H), 3.70-3.48 (m, 2H), 2.49-2.21 (m, 2H), 2.10 (d, J = 8.9 Hz, 3H)。

step b:

under nitrogen atmosphere, 1- [3- [ (4, 5-dichloro-2-hydroxyphenyl) carbonyl group]Pyrrolidin-1-yl radical]Ethan-1-one (0.48 g, 1.59 mmol), K₂CO₃ A mixture of (0.44 g, 3.18 mmol) and 1- (chloromethyl) -4-methoxybenzene (0.27 g, 1.75 mmol) in DMF (5 mL) was stirred at 80 ℃ for 1 h. After cooling to room temperature, the resulting mixture was diluted with water (20 mL) at room temperature. The resulting mixture was extracted with EA (3X 20 mL). The combined organic layers were washed with brine (5X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with DCM/MeOH (12/1) to give 1- [3- ([4, 5-dichloro-2- [ (4-methoxyphenyl) methoxy) as a pale yellow oil ]Phenyl radical]Carbonyl) pyrrolidin-1-yl]Ethan-1-one (0.49 g, 73%): C₂₁H₂₁Cl₂NO₄ [M + H]⁺Calculated lcms (esi): 422, 424 (3: 2), found 422, 424 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.78 (s, 1H), 7.51 (d, J = 7.0 Hz, 1H), 7.48-7.39 (m, 2H), 6.97 (dd, J =8.6, 2.0 Hz, 2H), 5.15 (s, 2H), 3.95 (dt, J = 23.3, 6.8 Hz, 1H), 3.82 (s, 3H), 3.63-3.51 (m, 1H), 3.51-3.36 (m, 3H), 3.26-3.17 (m, 1H), 2.14-1.93 (m, 4H)。

step c:

to a stirred 1- [3- ([4, 5-dichloro-2- [ (4-methoxyphenyl) methoxy) atmosphere at room temperature under a nitrogen atmosphere]Phenyl radical]Carbonyl) pyrrolidin-1-yl]To a solution of ethan-1-one (0.42 g, 0.99 mmol) and 2-methylpropane-2-sulfinamide (0.60 g, 4.97 mmol) in THF (5 mL) was added Ti (OEt)₄(1.81 g, 7.96 mmol). The resulting mixture was stirred at 70 ℃ for 16 hours under nitrogen atmosphere. The reaction was quenched with saturated NaHCO₃The aqueous solution (20 mL) was quenched at room temperature and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give N- [ (1-acetylpyrrolidin-3-yl) ([4, 5-dichloro-2- [ (4-methoxyphenyl) methoxy) as a pale yellow oil]Phenyl radical]) Methylene group]2-methylpropane-2-sulfinamide (0.81 g, crude), which is used directly in the subsequent step without further purification C₂₅H₃₀Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 525, 527 (3: 2), found 525, 527 (3: 2).

Step d:

to a stirred mixture of N- (1-acetylpyrrolidin-3-yl) ([4, 5-dichloro-2- [ (4-methoxyphenyl) methoxy) at room temperature ]Phenyl radical]) Methylene group](iii) -2-methylpropane-2-sulfinamide (0.81 g, 1.54 mmol) in MeOH (4 mL) to which NaBH was added₄(0.12 g, 3.08 mmol). The reaction was stirred at room temperature for 1 hour. The resulting solution was quenched with water (15 mL). The resulting mixture was extracted with EA (3X 20 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give N- [ (1-acetylpyrrolidin-3-yl) ([4, 5-dichloro-2- [ (4-methoxyphenyl) methoxy) as a pale yellow oil]Phenyl radical]) Methyl radical]2-methylpropane-2-sulfinamide (0.61 g, crude), which is used directly in the subsequent step without further purification C₂₅H₃₂Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 527, 529 (3: 2), found 527, 529 (3: 2).

Step e:

to a stirred mixture of N- [ (1-acetylpyrrolidin-3-yl) ([4, 5-dichloro-2- [ (4-methoxyphenyl) methoxy) at room temperature]Phenyl radical]) Methyl radical]To a mixture of-2-methylpropane-2-sulfinamide (0.61 g, 1.16 mmol) in 1, 4-dioxane (2 mL) was added aqueous HCl (4N, 2 mL). The reaction was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with DCM/MeOH (20/1) to give 1- [3- [ amino ([4, 5-dichloro-2- [ (4-methoxyphenyl) methoxy ] as a pale yellow oil ]Phenyl radical]) Methyl radical]Pyrrolidin-1-yl radical]Ethan-1-one (0.35 g, 58% of three steps total): C₂₁H₂₄Cl₂N₂O₃ [M + H]⁺Calculated lcms (esi): 423, 425 (3: 2), found 423, 425 (3: 2).

Step f:

1- [3- [ amino ([4, 5-dichloro-2- [ (4-methoxyphenyl) methoxy) methyl]Phenyl radical]) Methyl radical]Pyrrolidin-1-yl radical]A solution of ethan-1-one (90 mg, 0.21 mmol) and HCl (6N, 2 mL) was stirred at 80 ℃ for 3 hours. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XSelect CSH Prep C18 OBD column, 19X 250 mm, 5 μm; mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 20% B to 35% B in 5.5 minutes; a detector: UV 220/254 nm; retention time: RT (reverse transcription)₁4.70 min, RT₂5.00 minutes. The fractions containing the desired product were collected at 4.70 min, concentrated under reduced pressure to give compound 33 (2- (amino (pyrrolidin-3-yl) methyl) -4, 5-dichlorophenol trifluoroacetic acid diastereomer 2) (9 mg, 11%) as a pale yellow solid, C₁₁H₁₄Cl₂N₂O [M + H]⁺Calculated lcms (esi): 261, 263 (3: 2), found 261, 263 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.53 (s, 1H), 7.12 (s, 1H), 4.44 (d, J =10.2 Hz, 1H), 3.64-3.47 (m, 1H), 3.44-3.34 (m, 1H), 3.29-3.06 (m, 2H), 2.98-2.84 (m, 1H), 2.48-2.34 (m, 1H), 2.06-1.88 (m, 1H)； ¹⁹F NMR (282 MHz, CD₃OD) delta-77.00 fractions containing the desired product were collected over 5.00 min, concentrated under reduced pressure to give compound 32 (2- (amino (pyrrolidin-3-yl) methyl) -4, 5-dichlorophenol trifluoroacetic acid diastereomer 1) (12 mg, 15%) as a pale yellow solid, C ₁₁H₁₄Cl₂N₂O [M + H]⁺Lcms (esi) calculated value of (a): 261, 263 (3: 2), found 261, 263 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.52 (s, 1H), 7.12 (s, 1H), 4.49 (d, J =9.3 Hz, 1H), 3.76-3.57 (m, 1H), 3.48-3.37 (m, 1H), 3.31-3.16 (m, 3H), 1.97-1.81 (m, 1H), 1.80-1.62 (m, 1H)； ¹⁹F NMR (282 MHz, CD₃OD) δ -77.01.

EXAMPLE 104 Compound 35 (2- (amino (1-tosylpiperidin-4-yl) methyl) -4, 5-dichlorophenol)

Step a:

under nitrogen atmosphere at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.12 g, 0.29 mmol) and Et₃To a solution of N (58 mg, 0.58 mmol) in DCM (2 mL) was added 4-methylbenzene-1-sulfonyl chloride (60 mg, 0.31 mmol) portionwise. After stirring at room temperature for an additional 1 hour under nitrogen atmosphere, the reaction solution was quenched with water (30 mL) at room temperature and extracted with EA (2X 30 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE/EA (2/1) to give as a yellow oilN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([1- [ (4-Methylbenzene) sulfonyl group)]Piperidin-4-yl radical]) Methyl radical]2-methylpropane-2-sulfinamide (50 mg, 26%): C₂₆H₃₄Cl₂N₂O₄S₂ [M + H]⁺Calculated lcms (esi): 573, 575 (3: 2), found 573, 575 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.66 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7,41 (s, 1H), 7.14 (s, 1H), 6.19-6.02 (m, 1H), 5.48-5.29 (m, 2H), 4.60 (s, 2H), 4.50 (d, J = 8.8 Hz, 1H), 4.14 (d, J = 7.7 Hz, 1H), 3.87-3.77 (m, 1H), 3.74-3.65 (m, 1H), 2.45 (s, 3H), 2.37-2.12 (m, 2H), 1.77-1.67 (m, 1H), 1.43-1.28 (m, 3H), 1.112 (s, 9H)。

step b:

under nitrogen atmosphere at room temperature with stirring N- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([1- [ (4-Methylbenzene) sulfonyl group)]Piperidin-4-yl]) Methyl radical]-2-methylpropane-2-sulfinamide (50 mg, 0.09 mmol) and Pd (PPh)₃)₄(11 mg, 0.01 mmol) in THF (2 mL) was added NaBH₄(5 mg, 0.14 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. The resulting mixture was quenched with water (10 mL) at room temperature and extracted with EA (3X 20 mL). The combined organic layers were taken over with water (220 mL) and washed with anhydrous Na₂SO₄Dried and filtered. Concentrating the filtrate under reduced pressure to obtain crude productN- ((4, 5-dichloro-2-hydroxyphenyl) (1-toluenesulfonylpiperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide. The crude product was used without further purification in the subsequent step: c₂₃H₃₀Cl₂N₂O₄S₂ [M + H]⁺Calculated lcms (esi): 533, 535 (3: 2), found 533, 535 (3: 2).

Step c:

at room temperature toNTo a solution of (- (4, 5-dichloro-2-hydroxyphenyl) (1-tosylpiperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (crude) in 1, 4-dioxane (3 mL) was added aqueous HCl (6 mL)N3 mL). The reaction solution was stirred at room temperature for 2 hours. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column, 100A, 10 μm, 19 mm × 250 mm; mobile phase A: having a NH concentration of 20 mmol/L ₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 50% B to 88% B in 6.5 minutes; a detector: UV 254/210 nm; retention time: 6.20 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure, and yielded compound 35 (2- (amino (1-tosylpiperidin-4-yl) methyl) -4, 5-dichlorophenol) (12 mg, 35% two-step total) C as a yellow solid₁₉H₂₂Cl₂N₂O₃S [M + H]⁺Calculated lcms (esi): 429, 431 (3: 2), found 429, 431 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.64 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.18 (s, 1H), 6.85 (s, 1H), 3.95-3.69 (m, 3H), 2.45 (s, 3H), 2.33-2.11 (m, 2H), 2.03-1.92 (d, J = 13.0 Hz, 1H), 1.81-1.54 (m, 1H), 1.56-1.16 (m, 3H)。

example 105. Compound 36 (N- [ (2-Hydroxynaphthalen-1-yl) (piperidin-4-yl) methyl]Acetamide trifluoroacetic acid)

Step a:

to N- [ (2-hydroxynaphthalen-1-yl) (pyridin-4-yl) methyl at room temperature]To a solution of acetamide (intermediate 7, example 7) (0.10 g, 0.34 mmol) in MeOH (3 mL) was added PtO₂(7 mg, 0.03 mmol). The reaction mixture was degassed three times with hydrogen and stirred at room temperature under a hydrogen atmosphere (50 atm) for 18 hours. The mixture was filtered through Celite (Celite), and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD, 100A, 10 μm, 19 mm × 250 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 15% B to 35% B in 8 minutes; a detector: UV 254/210 nm; retention time: 6.67 minutes. The collected fractions containing the desired product were concentrated under reduced pressure to give compound 36 (a) as a pale yellow solid N- [ (2-Hydroxynaphthalen-1-yl) (piperidin-4-yl) methyl]Acetamide trifluoroacetic acid) (90 mg, 90%): C₁₈H₂₂N₂O₂ [M + H]⁺Calculated lcms (esi): 299, measured value 299;¹H NMR (400 MHz, CD₃OD) δ 8.20 (d, J = 8.6 Hz, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 5.85 (d, J =10.2 Hz, 1H), 3.55 (d, J = 12.4 Hz, 1H), 3.27 (d, J = 12.4 Hz, 1H), 3.07 (t, J = 12.8 Hz, 1H), 2.90-2.75 (m, 1H), 2.73-2.60 (m, 1H), 2.35-2.22 (d, J =14.4 Hz, 1H), 2.09 (s, 3H), 1.70-1.59 (m, 1H), 1.49-1.32 (m, 2H)； ¹⁹F-NMR (376 MHz, CD₃OD) δ -77.11.

example 106 Compound 34 (1- (amino (piperidin-4-yl) methyl) naphthalene-2-ol trifluoroacetic acid)

Step a:

subjecting N- ((2-hydroxynaphthalen-1-yl) (piperidin-4-yl) methyl) acetamide (free base of Compound 36)Example 105) (0.20 g, 0.67 mmol) in aqueous HCl (6)N5 mL) was stirred at 100 ℃ for 8 hours. After cooling to room temperature, the resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD, 100A, 10 μm, 19 mm × 250 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 5% B to 25% B in 6.5 minutes; a detector: UV 254/210 nm; retention time: 5.35 minutes. The fractions containing the desired product were collected and concentrated to give compound 34 (1- (amino (piperidin-4-yl) methyl) naphthalen-2-ol trifluoroacetic acid) (2 mg, 1%) C as a grey solid₁₆H₂₀N₂O [M + H]⁺Calculated lcms (esi): 257, found 257;¹H NMR (400 MHz, CD₃OD) δ 8.07 (d, J = 8.7 Hz, 1H), 7.93 (t, J = 7.8 Hz, 2H), 7.63 (t, J = 7.7 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.28 (d, J = 9.0 Hz, 1H), 5.05 (d, J = 9.7 Hz, 1H), 3.65 (d, J = 12.6 Hz, 1H), 3.31 (d, J = 12.6 Hz, 1H), 3.14 (t, J = 12.5 Hz, 1H), 2.94-2.75 (m, 2H), 2.41 (d, J = 14.2 Hz, 1H), 1.87-1.68 (m, 1H), 1.56-1.39 (m, 2H)； ¹⁹F-NMR (376 MHz, CD₃OD) δ -76.97.

EXAMPLE 107 Compound 37 (2- [ amino (piperidin-4-yl) methyl ] -3,4, 5-trichlorophenol trifluoroacetic acid)

Step a:

to a stirred mixture of 3,4, 5-trichlorophenol (example 9, step a) (0.59 g, 2.99 mmol), acetamide (0.21 g, 3.59 mmol) and pyridine-4-carbaldehyde (0.32 g, 2.99 mmol) was added AlCl at room temperature under a nitrogen atmosphere ₃(0.06 g, 0.45 mmol). The reaction was stirred at 110 ℃ for 16 hours. The reaction was quenched with water (25 mL) at room temperature and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Passing the residue through a reverse phaseChromatographic purification, eluting with 50% aqueous ACN (plus 0.05% TFA) to give a pale yellow oilN- [ pyridin-4-yl (2,3, 4-trichloro-6-hydroxyphenyl) methyl group]Acetamide (0.14 g, 12%): C₁₄H₁₁Cl₃N₂O₂ [M + H]⁺Calculated lcms (esi): 345, 347, 349 (3: 3: 1), found 345, 347, 349 (3: 3: 1);¹H NMR (300 MHz, CD₃OD) δ 8.79-8.70 (m, 2H), 7.94-7.85 (m, 2H), 7.13 (s, 1H), 7.05 (s, 1H), 2.17 (s, 3H)。

step b:

to N- [ pyridin-4-yl (2,3, 4-trichloro-6-hydroxyphenyl) methyl at room temperature]To a solution of acetamide (0.10 g, 0.29 mmol) in 20 mL MeOH/AcOH (v/v = 1/1) was added PtO₂(20 mg, 0.09 mmol). The mixture was stirred at 30 ℃ for 6 hours under a hydrogen atmosphere (50 atm). The reaction was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in EA (20 mL) and water (20 mL). The aqueous layer was extracted with EA (3X 20 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to obtain a colorless oilN- [ piperidin-4-yl (2,3, 4-trichloro-6-hydroxyphenyl) methyl group ]Acetamide (0.10 g, crude), which was used in the next step without further purification: c₁₄H₁₇Cl₃N₂O₂ [M + H]⁺Calculated lcms (esi): 351, 353, 355 (3: 3: 1), found 351, 353, 355 (3: 3: 1);¹H NMR (300 MHz, CD₃OD) δ 7.04-6.87 (m, 1H), 5.51 (d, J =z, 1H), 3.52-3.38 (m, 2H), 3.06-2.78 (m, 2H), 2.54-2.03 (m, 2H), 1.98 (s, 3H), 1.61-1.42 (m, 3H) for 10.5 hours.

Step c:

will be provided withN- [ piperidin-4-yl (2,3, 4-trichloro-6-hydroxyphenyl) methyl group]A solution of acetamide (0.10 g, 0.29 mmol) in concentrated HCl (3 mL) was stirred at 100 ℃ for 3 hours. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100, 10 μm, 19 mm × 250 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 20 mL/min; gradient: within 8 minutesFrom 5% B to 40% B; a detector: UV 254/210 nm; retention time: 7.18 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure, and yielded compound 37 (2- [ amino (piperidin-4-yl) methyl) as a pale yellow solid]-3,4, 5-trichlorophenol trifluoroacetic acid) (70 mg, 57% of two steps in total) C₁₂H₁₅Cl₃N₂O [M + H]⁺Calculated lcms (esi): 309, 311, 313 (3: 3: 1), found 309, 311, 313 (3: 3: 1);¹H NMR (400 MHz, CD₃OD) δ 7.15 (s, 1H), 4.69 (d, J = 10.1 Hz, 1H), 3.55 (d, J = 12.9 Hz, 1H), 3.42-3.35 (m, 1H), 3.05 (td, J = 13.1, 3.1 Hz, 1H), 3.00-2.88 (m, 1H), 2.76-2.63 (m, 1H), 2.26 (d, J = 14.0 Hz, 1H), 1.77-1.62 (m, 1H), 1.62-1.50 (m, 2H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.06.

example 108 Compound 38 (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-2-one trifluoroacetic acid diastereomer 1) and Compound 39 (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-2-one diastereomer 2)

A, step a:

under nitrogen, 3, 4-dichlorophenol (2.00 g, 12.27 mmol), 6-bromopyridine-3-carbaldehyde (2.30 g, 12.27 mmol), acetamide (0.87 g, 14.72 mmol) and AlCl₃(0.245 g, 1.84 mmol) of the mixture was stirred at 110 ℃ for 1.5 h. After cooling to room temperature, the mixture was diluted with water (80 mL) and extracted with EA (5X 50 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with PE/EA (2/3) to give N- [ (6-bromopyridin-3-yl) (4, 5-dichloro-2-hydroxyphenyl) methyl group as a pale yellow solid]Acetamide (1.21 g, 20%): C₁₄H₁₁BrCl₂N₂O₂ [M + H]⁺Calculated lcms (esi): 389, 391, 393 (2: 3: 1), found 389, 391, 393 (2:3 : 1)； ¹H NMR (400 MHz, DMSO-d ₆) δ 10.59 (s, 1H), 8.47 (d, J = 8.4 Hz, 1H), 8.24 (dd, J = 7.3, 2.6 Hz, 1H), 7.69-7.57 (m, 1H), 7.56-7.42 (m, 2H), 6.90-6.80 (m, 2H), 1.99 (s, 3H)。

step b:

under nitrogen atmosphere, N- [ (6-bromopyridin-3-yl) (4, 5-dichloro-2-hydroxyphenyl) methyl group]Acetamide (0.51 g, 1.32 mmol), (b), (c) and (d)E)-N- (Phenylmethylene) hydroxylamine (0.21 g, 1.71 mmol), Pd₂(dba)₃(0.12 g, 0.13 mmol), RockPhos (0.12 g, 0.26 mmol) and Cs₂CO₃A mixture of (0.94 g, 2.9 mmol) in DMF (5 mL)) was stirred at 80 ℃ for 2 h. The reaction mixture was cooled to ambient temperature, quenched with water (30 mL), and extracted with DCM/MeOH (10/1, 3X 50 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na ₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel eluting with DCM/MeOH (10:1) to give N- [ (4, 5-dichloro-2-hydroxyphenyl) (6-hydroxypyridin-3-yl) methyl ] as a pale yellow oil]Acetamide (0.26 g, 60%): C₁₄H₁₂Cl₂N₂O₃ [M + H]⁺Calculated lcms (esi): 327, 329 (3: 2), found 327, 329 (3: 2).

Step c:

under nitrogen atmosphere, the mixture isN- [ (4, 5-dichloro-2-hydroxyphenyl) (6-hydroxypyridin-3-yl) methyl]Acetamide (65 mg) in aqueous HCl (6)N2 mL) was stirred at 80 ℃ for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC under the following conditions: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase A: has 20 mmoL/L NH₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 15% B to 68% B in 6.5 minutes; a detector: UV 254/220 nm; retention time: 5.07 minutes. The combined product-containing fractions were concentrated under reduced pressure to give 5- [ amino (4, 5-dichloro-2-hydroxyphenyl) methyl ester as an off-white solid]-1, 2-dihydropyridin-2-one (20 mg, 35%): C₁₂H₁₀Cl₂N₂O₂ [M + H]⁺Calculated lcms (esi): 285, 287 (3: 2), found 285, 287 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.64 (dd, J = 9.5, 2.7 Hz, 1H), 7.41 (d, J = 2.6 Hz, 1H), 7.33 (s, 1H), 6.92 (s, 1H), 6.54 (d, J =9.6 Hz, 1H), 5.15 (s, 1H)。

step d:

Reacting 5- [ amino (4, 5-dichloro-2-hydroxyphenyl) methyl]-1, 2-dihydropyridin-2-one (70 mg, 0.25 mmol) and PtO₂(7 mg, 0.03 mmol) in aqueous HCl (1)N0.1 mL) and MeOH (1 mL) under a hydrogen atmosphere (50 atm) at room temperature for 6.5 hours. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC on column: xbridge C18 OBD Prep Column, 100A, 10 μm, 19 mm × 250 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 8% B to 40% B in 6.5 minutes; a detector: UV 254/210 nm; retention time: RT (reverse transcription)₁5.33 min, RT₂5.72 minutes.

The faster eluting enantiomer was obtained as compound 38 (diastereomer 1 of 5- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-2-one trifluoroacetic acid) (4.5 mg, 6%) as an off white solid at 5.33 min C₁₂H₁₄Cl₂N₂O₂ [M + H]⁺Calculated lcms (esi): 289, 291 (3: 2), found 289, 291 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.46 (s, 1H), 7.10 (s, 1H), 4.28 (d, J = 10.2 Hz, 1H), 3.03-2.85 (m, 2H), 2.74-2.58 (m, 1H), 2.55-2.35 (m, 2H), 2.19 (d, J = 13.4 Hz, 1H), 1.85-1.65 (m, 1H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -76.98.

the slower eluting enantiomer containing the impurity at 5.72 min was repurified by preparative HPLC under the following conditions: xbridge C18 OBD Prep Column, 100A, 10 μm, 19 mm × 250 mm; mobile phase A: having a NH concentration of 10 mmol/L ₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 8% B to 60% B in 6.5 min; a detector: UV 254/210nm; retention time: 5.92 minutes. The combined product-containing fractions were concentrated under reduced pressure to give compound 39 (5- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-2-one diastereomer 2) (2.8 mg, 3%) as an off-white solid C₁₂H₁₄Cl₂N₂O₂ [M + H]⁺Calculated lcms (esi): 289, 291 (3: 2), found 289, 291 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.32 (s, 1H), 6.91 (s, 1H), 4.02 (d, J = 8.3 Hz, 1H), 3.57-3.49 (m, 1H), 3.17 (dd, J = 12.4, 10.2 Hz, 1H), 2.41-2.18 (m, 3H), 1.67-1.63 (m, 1H), 1.57-1.43 (m, 1H)。

EXAMPLE 109 Compound 40 (2- [ 1-amino-1- (piperidin-4-yl) ethyl ] -4, 5-dichlorophenol)

Step a:

stirring CH at-78 deg.C under argon₃A solution of Li (1.4 mL, 2.31 mmol, 1.6M in ether) in toluene (2 mL) was added dropwiseN-[(1Z) - (1-acetylpiperidin-4-yl) (4, 5-dichloro-2-methoxyphenyl) methylene]2-methylpropane-2-sulfinamide (0.50 g, 1.15 mmol) and AlMe₃(0.17 g, 2.31 mmol) in THF (10 mL). The reaction was stirred at-78 ℃ for 8 hours. The reaction mixture was quenched with water (20 mL) at-78 ℃. The aqueous layer was extracted with EA (3X 20 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with DCM/MeOH (20/1) to give N- [1- (1-acetylpiperidin-4-yl) -1- (4, 5-dichloro-2-methoxyphenyl) ethyl as a pale yellow solid ]2-methylpropane-2-sulfinamide (0.10 g, 19%): C₂₀H₃₀Cl₂N₂O₃S [M + H]⁺Lcms (esi) calculated value of (a): 449, 451 (3: 2), found 449, 451 (3: 2).

Step b:

at room temperature with stirringN- [1- (1-acetylpiperidin-4-yl) -1- (4, 5-dichloro-2-methoxyphenyl) ethyl]To a solution of (2-methylpropane-2-sulfinamide) (0.10 g, 0.22 mmol) in DCM (2 mL) was added BBr₃(0.33 g, 1.34 mmol). The reaction was stirred at room temperature for 2 hours. The reaction solution was quenched with water (1 mL) and concentrated under reduced pressure to give 1- [4- [ 1-amino-1- (4, 5-dichloro-2-hydroxyphenyl) ethyl ester as a pale yellow oil]Piperidin-1-yl radical]Ethan-1-one (0.10 g, crude), which was used in the next step without further purification: c₁₅H₂₀C_l2N₂O₂ [M + H]⁺Calculated lcms (esi): 331, 333 (3: 2), found 331, 333 (3: 2).

Step c:

1- [4- [ 1-amino-1- (4, 5-dichloro-2-hydroxyphenyl) ethyl]Piperidin-1-yl radical]Ethan-1-one (0.10 g, 0.30 mmol) in aqueous HCl (6)N4 mL) was stirred at 100 ℃ for 3 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase A: has 10 mmoL/L NH₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 15% B to 50% B in 8 minutes; a detector: UV 254/210 nm; retention time: 6.65 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure, and yielded compound 40 (2- [ 1-amino-1- (piperidin-4-yl) ethyl) as a pale yellow solid ]-4, 5-dichlorophenol) (35 mg, 55% of the total of the two steps): C₁₃H₁₈Cl₂N₂O [M + H]⁺Lcms (esi) calculated value of (a): 289, 291 (3: 2), found 289, 291 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.15 (s, 1H), 6.78 (s, 1H), 3.29-3.14 (m, 2H), 2.84-2.61 (m, 2H), 2.21-2.03 (m, 1H), 1.98-1.82 (m, 1H), 1.74-1.64 (m, 1H), 1.56 (s, 3H), 1.46-1.28 (m, 2H)。

EXAMPLE 110 Compound 41 (2- (amino (1-benzylpiperidin-4-yl) methyl) -4, 5-dichlorophenol trifluoroacetic acid)

A, step a:

at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl](bromomethyl) benzene (49 mg, 0.29 mmol) was added portionwise to a mixture of-2-methylpropane-2-sulfinamide (0.10 g, 0.24 mmol) and DIPEA (46 mg, 0.36 mmol) in ACN (5 mL). The reaction solution was stirred at room temperature for 1 hour. The resulting solution was diluted with water (30 mL) at room temperature and extracted with EA (2X 30 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with DCM/MeOH (25/1) to give as a yellow oilN- [ (1-Benzylpiperidin-4-yl) [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]-2-methylpropane-2-sulfinamide (31 mg, 26%): C₂₆H₃₄Cl₂N₂O₂S [M + H]⁺Calculated lcms (esi): 509, 511 (3: 2), found 509, 511 (3: 2);¹H NMR (300 MHz, DMSO-d ₆) δ 7.56 (s, 1H), 7.36-7.18 (m, 6H), 6.10-5.94 (m, 1H), 5.53-5.23 (m, 3H), 4.63 (d, J = 4.8 Hz, 2H), 4.53-4.42 (m, 1H), 3.50 (s, 2H), 2.93-2.67 (m, 2H), 1.98-1.57 (m, 4H), 1.31-1.14 (m, 3H), 1.12 (s, 9H)。

step b:

under nitrogen atmosphere at room temperature with stirring N- [ (1-Benzylpiperidin-4-yl) [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]-2-methylpropane-2-sulfinamide (31 mg, 0.06 mmol) and Pd (PPh)₃)₄(7 mg, 0.006 mmol) to a mixture in THF (2 mL) NaBH was added₄(4 mg, 0.09 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. The reaction mixture was quenched with water (10 mL) at room temperature. The aqueous layer was extracted with EA (3X 20 mL). The combined organic layers were washed with water (2X 20 mL) and dried over anhydrous Na₂SO₄Dried and filtered. Concentrating the filtrate under reduced pressure to obtain crude productN- ((1-benzylpiperidin-4-yl) (4, 5-dichloro-2-hydroxyphenyl) methyl) -2-methylpropane-2-sulfinamide. The crude product was used without further purification in the subsequent step: c₂₃H₃₀Cl₂N₂O₂S [M + H]⁺Calculated lcms (esi): 469, 471 (3: 2), found 469, 471 (3: 2).

Step c:

at room temperature toNTo a solution of (- (1-benzylpiperidin-4-yl) (4, 5-dichloro-2-hydroxyphenyl) methyl) -2-methylpropane-2-sulfinamide (crude) in 1, 4-dioxane (3 mL) was added aqueous HCl (6 mL)N3 mL). The reaction solution was stirred at room temperature for 2 hours. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XSelect CSH Prep C18 OBD column, 19X 250 mm, 5 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 10% B to 60% B in 6.5 minutes; a detector: UV 254 nm; retention time: 5.9 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure to give compound 41 (2- (amino (1-benzylpiperidin-4-yl) methyl) -4, 5-dichlorophenol trifluoroacetic acid) (12.4 mg, 43% two steps total) C as an off-white solid ₁₉H₂₂Cl₂N₂O [M + H]⁺Lcms (esi) calculated value of (a): 365, 367 (3: 2), found 365, 367 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.62-7.40 (m, 6H), 7.11 (s, 1H), 4.37-4.28 (m, 3H), 3.67-3.58 (m, 1H), 3.54-3.44 (m, 1H), 3.17-2.91 (m, 2H), 2.55-2.38 (m, 1H), 2.32-2.15 (m, 1H), 1.83-1.44 (m, 3H)； ¹⁹F NMR (282, CD₃OD) δ -76.98.

EXAMPLE 111 Compound 42 (2- [ amino (8-azabicyclo [3.2.1] oct-3-yl) methyl ] -4, 5-dichlorophenol trifluoroacetic acid)

A, step a:

to a stirred solution of 1-bromo-4, 5-dichloro-2- (prop-2-en-1-yloxy) benzene (example 6, step b) (0.71 g, 2.51 mmol) in THF (8 mL) at 0 deg.C under a nitrogen atmosphere was added dropwisei-PrMgCl (1.68 mL, 3.36 mmol, 2M in THF). The reaction was stirred at 0 ℃ for 30 minutes. Then will be3- [ methoxy (methyl) carbamoyl]-8-azabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (0.50 g, 1.68 mmol) was added to the reaction. The reaction was stirred at 0 ℃ for 1 hour. Reacting with saturated NH₄Aqueous Cl (5 mL) was quenched and diluted with EA (50 mL) and water (30 mL). The aqueous layer was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography, eluting with PE/EA (5/1), and obtaining 3- [ [2- (but-3-en-1-yl) -4, 5-dichlorophenyl group as pale yellow oil]Carbonyl radical]-8-azabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (0.32 g, 40%): C₂₂H₂₇Cl₂NO₄ [M + Na]⁺Calculated lcms (esi): 462, 464 (3: 2), found 462, 464 (3: 2);

Step b:

to a stirred 3- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl group at room temperature under a nitrogen atmosphere]Carbonyl radical]-8-azabicyclo [3.2.1]To a solution of tert-butyl octane-8-carboxylate (0.25 g, 0.57 mmol) and tert-butanesulfinamide (83 g, 0.68 mmol) in THF (5 mL) was added Ti (OEt)₄(0.26 g, 1.14 mmol). The reaction was stirred at 70 ℃ for 16 hours. After cooling to room temperature, the reaction solution was taken up with saturated Na₂CO₃Aqueous solution (30 mL) was quenched. The resulting mixture was filtered through celite (celite), the filtrate was diluted with EA (30 mL) and water (30 mL), and the aqueous layer was then extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography, eluting with PE/EA (5/1), to obtain 3- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] as a yellow solid][ (2-methylpropane-2-sulfinyl) imino]Methyl radical]-8-azabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (0.26 g, 76%): C₂₆H₃₆C_l2N₂O₄S [M + Na]⁺Calculated lcms (esi): 565, 567 (3: 2), found 565, 567 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.41 (s, 1H), 7.24 (s, 1H), 6.12-5.99 (m, 1H), 5.43 (d, J = 17.2 Hz, 1H), 5.31 (dd, J = 10.6, 1.6 Hz, 1H), 4.64 (d, J = 5.1 Hz, 2H), 4.28-4.16 (m, 2H), 3.31-3.22 (m, 1H), 2.05-1.91 (m, 3H), 1.87-1.66 (m, 5H), 1.48 (s, 9H), 1.22 (s, 9H)。

step c:

to a stirred 3- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl group at room temperature ][ (2-methylpropane-2-sulfinyl) imino ] methane]Methyl radical]-8-azabicyclo [3.2.1]To a solution of octane-8-carboxylic acid tert-butyl ester (0.20 g, 0.37 mmol) in MeOH (5 mL) was added NaBH₄(28 mg, 0.74 mmol). Saturated NH is used for reaction₄Aqueous Cl (2 mL) was quenched and diluted with EA (30 mL) and water (30 mL). The aqueous layer was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 3- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] as a pale yellow solid][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]-8-azabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (0.20 g, crude), which was used in the next step without further purification: c₂₆H₃₈Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 545, 547 (3: 2), found 545, 547 (3: 2).

Step d:

to a stirred 3- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl group at room temperature][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]-8-azabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (0.20 g, 0.37 mmol) and Pd (PPh)₃)₄(4 mg, 0.004 mmol) in THF (5 mL) NaBH was added₄(28 mg, 0.73 mmol). The reaction was stirred at room temperature for 30 minutes. Reacting with saturated NH ₄Aqueous Cl (1 mL) was quenched and concentrated under reduced pressure. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE/EA (1/1) to give 3- [ (4, 5-dichloro-2-hydroxyphenyl) [ (2-methylpropane-2-sulfinyl) amino]Methyl radical]-8-azabicyclo [3.2.1]Octane-8-carboxylic acid tert-butyl ester (0.13 g, 54% of two stages in total): C₂₃H₃₄Cl₂N₂O₄S [M + Na]⁺Calculated lcms (esi): 527, 529 (3: 2), trueMeasured value 527, 529 (3: 2);¹H NMR (300 MHz, CD3OD) δ 7.40 (s, 1H), 6.91 (s, 1H), 4.30-4.00 (m, 3H), 2.42 (s, 1H), 1.97-1.80 (m, 4H), 1.80-1.54 (m, 2H), 1.52-1.43 (m, 10H), 1.27-1.19 (m, 10H)。

step e:

to a stirred mixture of 3- [ (4, 5-dichloro-2-hydroxyphenyl) [ (2-methylpropane-2-sulfinyl) amino group at room temperature]Methyl radical]-8-azabicyclo [3.2.1]To a solution of tert-butyl octane-8-carboxylate (0.13 g, 0.26 mmol) in 1, 4-dioxane (2 mL) was added aqueous HCl (4 g/g)N1 mL). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The mixture was then dissolved in DCM (2 mL) and TFA (0.5 mL) was added at room temperature. The resulting solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 5% B to 60% B in 6.50 minutes; a detector: UV 254/210 nm; retention time: 5.40 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure to give compound 42 (2- [ amino (8-azabicyclo [3.2.1 ] amino) as a pale pink solid ]Octane-3-yl) methyl]-4, 5-dichlorophenol trifluoroacetic acid) (37.7 mg, 47%): C₁₄H₁₈Cl₂N₂O [M + H]⁺Calculated lcms (esi): 301, 303 (3: 2), found 301, 303 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.45 (s, 1H), 7.10 (s, 1H), 4.28-4.09 (m, 2H), 4.06-3.88 (m, 1H), 2.77-2.55 (m, 1H), 2.23-1.99 (m, 4H), 1.99-1.70 (m, 2H), 1.70-1.27 (m, 2H)； ¹⁹F NMR (282 MHz, CD₃OD) δ -76.95.

EXAMPLE 112 Compound 43 (1- [4- [ amino (4, 5-dichloro-2-hydroxyphenyl) methyl ] piperidin-1-yl ] -2-methylpropan-1-one trifluoroacetic acid)

Step a:

in nitrogenTo a stirred solution of HATU (0.27 g, 0.72 mmol) and 2-methylpropionic acid (63 mg, 0.72 mmol) in DMF (5 mL) at room temperature under an atmosphere was addedN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.10 g, 0.24 mmol) and Et₃N (72 mg, 0.72 mmol). The resulting solution was quenched with water (30 mL) at room temperature and extracted with EA (3X 40 mL) under nitrogen at room temperature for 2 h of stirring. The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with a solution containing 10 mmol/L NH₄HCO₃Is eluted in 70% aqueous ACN and is obtained in the form of a pale yellow oilN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (2-Methylpropionyl) piperidin-4-yl group]Methyl radical]-2-methylpropane-2-sulfinamide (70 mg, 60%): C ₂₃H₃₄Cl₂N₂O₃S [M + H]⁺Lcms (esi) calculated value of (a): 489, 491 (3: 2), found 489, 491 (3: 2).

Step b:

under nitrogen atmosphere at room temperature with stirringN- [ (4, 5-dichloro-2-hydroxyphenyl) [1- (2-methylpropanoyl) piperidin-4-yl]Methyl radical]-2-methylpropane-2-sulfinamide (70 mg, 0.16 mmol) and Pd (PPh)₃)₄(2 mg, 0.002 mmol) in THF (2 mL) NaBH was added₄(12 mg, 0.31 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. The resulting mixture was quenched with water (20 mL) and extracted with EA (3X 20 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. Filtering, and concentrating the filtrate under reduced pressure to obtainN- ((4, 5-dichloro-2-hydroxyphenyl) (1-isobutyrylpiperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide. The crude product was used without further purification in the subsequent step: c₂₀H₃₀Cl₂N₂O₃S [M + H]⁺Calculated lcms (esi): 449, 451 (3: 2), found 449, 451 (3: 2).

Step c:

stirring at room temperatureIs/are as followsNTo a solution of (- (4, 5-dichloro-2-hydroxyphenyl) (1-isobutyrylpiperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (crude) in 1, 4-dioxane (3 mL) was added aqueous HCl (6)N1 mL). The reaction solution was stirred at room temperature for 2 hours. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 23% B to 45% B in 9 minutes; a detector: UV 254/210 nm; retention time: 6.58 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 43 (1- [4- [ amino (4, 5-dichloro-2-hydroxyphenyl) methyl ] as a pink solid ]Piperidin-1-yl radical]-2-methylpropan-1-one trifluoroacetic acid) (12.0 mg, 22% in two steps total): C₁₆H₂₂Cl₂N₂O₂ [M + H]⁺Calculated lcms (esi): 345, 347 (3: 2), found 345, 347 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.43 (d, J = 3.3 Hz, 1H), 7.08 (s, 1H), 4.73-4.50 (m, 1H), 4.21-3.98 (m, 2H), 3.14-2.89 (m, 2H), 2.69-2.29 (m, 2H), 2.09-1.93 (m, 1H), 1.43-1.15 (m, 3H), 1.15-0.95 (q, J = 6.6 Hz, 6H)； ¹⁹F-NMR (282 MHz, CD₃OD) δ -76.98.

example 113 Compound 44 (2- (amino (1- (tetrahydro-2))H-pyran-4-yl) piperidin-4-yl) methyl) -4, 5-dichlorophenol

Step a:

at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide (0.20 g, 0.48 mmol), HOAc (29 mg, 0.48 mmol) and dihydro-2HPyran-4 (3)H) To a mixture of-ketones (96 mg, 0.95 mmol) in DCM (5 mL) was added NaBH (OAc) in portions₃(0.30 g, 1.43 mmol). The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with water (30 mL) at room temperatureExtracted with EA (2X 30 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography with a solution having 10 mmol/L NH₄HCO₃Is eluted in 50% aqueous ACN and is obtained in the form of a yellow oilN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (Oxocyclohexan-4-yl) piperidin-4-yl]Methyl radical]2-methylpropane-2-sulfinamide (0.20 g, 75%): C ₂₄H₃₆Cl₂N₂O₃S [M + H]⁺Lcms (esi) calculated value of (a): 503, 505 (3: 2), and actually measured values 503, 505 (3: 2).

Step b:

under nitrogen atmosphere, stirred at room temperatureN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (Oxocyclohexan-4-yl) piperidin-4-yl]Methyl radical]-2-methylpropane-2-sulfinamide (0.20 mg, 0.46 mmol) and Pd (PPh)₃)₄(0.11 g, 0.09 mmol) in THF (3 mL) was added NaBH in portions₄(35 mg, 0.92 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. The resulting mixture was quenched with water (20 mL) at room temperature and extracted with EA (3X 20 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. Filtering, and concentrating the filtrate under reduced pressure to obtainN- ((4, 5-dichloro-2-hydroxyphenyl) (1- (tetrahydro-2)H-pyran-4-yl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide. The crude product was used without further purification in the subsequent step: c₂₁H₃₂Cl₂N₂O₃S [M + H]⁺Calculated lcms (esi): 463, 465 (3: 2), found 463, 465 (3: 2).

Step c:

at room temperature toN- ((4, 5-dichloro-2-hydroxyphenyl) (1- (tetrahydro-2)H-pyran-4-yl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (crude) to a solution in 1, 4-dioxane (3 mL) was added aqueous HCl (6 N3 mL). The reaction solution was stirred at room temperature for 2 hours. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column, 100A, 10 μm, 19 mm × 250 mm; mobile phase A: having a NH concentration of 20 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 30% B to 40% B in 9 minutes; a detector: UV 254/210 nm; retention time: 7.28 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure to give compound 44 (2- (amino (1- (tetrahydro-2-yl) amino) as an off-white solidH-pyran-4-yl) piperidin-4-yl) methyl) -4, 5-dichlorophenol) (28 mg, 17% two-step total): C₁₇H₂₄Cl₂N₂O₂ [M + H]⁺Calculated lcms (esi): 359, 361 (3: 2), found 359, 361 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.19 (s, 1H), 6.85 (s, 1H), 3.99 (d, J = 11.9 Hz, 2H), 3.89 (d, J = 8.0 Hz, 1H), 3.46-3.35 (m, 2H), 3.12 (d, J = 11.4 Hz, 1H), 3.02 (d, J = 11.4 Hz, 1H), 2.61-2.43 (m, 1H), 2.27-2.06 (m, 2H), 2.00 (d, J = 13.4 Hz, 1H), 1.86-1.73 (m, 3H), 1.62-1.23 (m, 5H)。

EXAMPLE 114 Compound 45 (2- (amino (1- (pyrrolidin-1-ylsulfonyl) piperidin-4-yl) methyl) -4, 5-dichlorophenol trifluoroacetic acid)

Step a:

under nitrogen atmosphere at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide (0.28 g, 0.67 mmol) and Et₃To a solution of N (0.20 g, 2.00 mmol) in DCM (5 mL) was added pyrrolidine-1-sulfonyl chloride (0.34 g, 2.00 mmol) in portions. The reaction solution was stirred at room temperature under nitrogen atmosphere for 1 hour. The resulting solution was quenched with water (30 mL) at room temperature, extracted with DCM (3X 20 mL), and purified over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography using a column containing 20 mmol/L NH₄HCO₃Eluting with 40-80% ACN water solution to obtain yellow solidN-[[4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (pyrrolidine-1-sulfonyl) piperidin-4-yl group]Methyl radical]2-methylpropane-2-sulfinamide (0.30 g, 73%): C₂₃H₃₅Cl₂N₃O₄S₂ [M + H]⁺Calculated lcms (esi): 552, 554 (3: 2), found 552, 554 (3: 2).

Step b:

under nitrogen atmosphere at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (pyrrolidine-1-sulfonyl) piperidin-4-yl group]Methyl radical]-2-methylpropane-2-sulfinamide (0.30 g, 0.54 mmol) and Pd (PPh)₃)₄(13 mg, 0.01 mmol) in THF (3 mL) was added NaBH in portions₄(41 mg, 1.09 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. The resulting mixture was quenched with water (20 mL) at room temperature and extracted with EA (3X 20 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. Filtering, and concentrating the filtrate under reduced pressure to obtain crude productN- ((4, 5-dichloro-2-hydroxyphenyl) (1- (pyrrolidin-1-ylsulfonyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide. The crude product was used without further purification in the subsequent step: c ₂₀H₃₁Cl₂N₃O₄S₂ [M + H]⁺Lcms (esi) calculated value of (a): 512, 514 (3: 2), found 512, 514 (3: 2).

Step c:

at room temperature with stirringNTo a solution of (- ((4, 5-dichloro-2-hydroxyphenyl) (1- (pyrrolidin-1-ylsulfonyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (crude) in 1, 4-dioxane (2 mL) was added aqueous HCl (6 mL)N1.5 mL). The reaction solution was stirred at room temperature for 2 hours. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column, 100A, 10 μm, 19 mm × 250 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 21% B to 58% B in 6.5 minutes; a detector: UV 254/210 nm; retention time: 5.80 minutes. Collecting the fractions containing the desired product and concentrating under reduced pressureCompound 45 (2- (amino (1- (pyrrolidin-1-ylsulfonyl) piperidin-4-yl) methyl) -4, 5-dichlorophenol trifluoroacetic acid) (30 mg, 18% two-step total) C is obtained as an off-white solid₁₆H₂₃Cl₂N₃O₃S [M + H]⁺Calculated lcms (esi): 408, 410 (3: 2), found 408, 410 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.44 (s, 1H), 7.08 (s, 1H), 4.17 (d, J = 9.9 Hz, 1H), 3.81 (d, J = 12.7 Hz, 1H), 3.67 (d, J = 12.7 Hz, 1H), 3.35-3.24 (m, 4H), 2.85 (td, J = 12.5, 2.6 Hz, 1H), 2.73 (td, J = 12.3, 3.1 Hz, 1H), 2.27-2.12 (m, 1H), 2.09-1.87 (m, 5H), 1.54-1.24 (m, 3H)； ¹⁹F-NMR (376 MHz, CD₃OD) δ -76.95.

EXAMPLE 115 Compound 46 (4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) -N,N-dimethylpiperidine-1-carboxamide)

A, step a:

under nitrogen atmosphere, stirred at room temperatureN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.17 g, 0.41 mmol) and Et₃A solution of N (0.12 g, 1.22 mmol) in DCM (3 mL, 47.19 mmol) was added portionwiseN,NDimethylcarbamoyl chloride (0.13 g, 1.22 mmol). The reaction solution was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction solution was quenched with water (30 mL) at room temperature and extracted with EA (2X 30 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE/EA (1/1) to give 4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] as a yellow solid][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]-N,N-dimethylpiperidine-1-carboxamide (80 mg, 36%): C₂₂H₃₃Cl₂N₃O₃S [M + H]⁺LCMS (ESI) meterCalculating the value: 490, 492 (3: 2), found 490, 492 (3: 2).

Step b:

to a stirred 4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl group at room temperature under a nitrogen atmosphere][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]-N,N-dimethylpiperidine-1-carboxamide (80 mg, 0.16 mmol) and Pd (PPh) ₃)₄(38 mg, 0.03 mmol) in THF (2 mL) was added NaBH in portions₄(25 mg, 0.65 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with water (20 mL) at room temperature and extracted with EA (3X 20 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 4- ((4, 5-dichloro-2-hydroxyphenyl) (1, 1-dimethylethylenesulfonamido) methyl) -N,N-dimethylpiperidine-1-carboxamide. The crude product was used without further purification in the subsequent step: c₁₉H₂₉Cl₂N₃O₃S [M + H]⁺Calculated lcms (esi): 450, 452 (3: 2), found 450, 452 (3: 2).

Step c:

stirring of 4- ((4, 5-dichloro-2-hydroxyphenyl) (1, 1-dimethylethylenesulfonamido) methyl) -N,N-dimethyl piperidine-1-carboxamide (crude) solution in 1, 4-dioxane (2 mL) aqueous HCl (6) was addedN1.5 mL). The reaction solution was stirred at room temperature for 2 hours. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column, 100A, 10 μm, 19 mm × 250 mm; mobile phase A: having a NH concentration of 20 mmol/L ₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 23% B to 70% B in 6.5 minutes; a detector: UV 254/210 nm; retention time: 6.12 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 46 (4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) -N,N-dimethylpiperidine-1-carboxamide) (18 mg, 37% in two steps in total): C₁₅H₂₁Cl₂N₃O₂ [M + H]⁺Calculated lcms (esi): 346, 348 (3: 2), found 346, 348 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.21 (s, 1H), 6.85 (s, 1H), 3.89 (d, J = 7.5 Hz, 1H), 3.81-3.71 (m, 1H), 3.68-3.59 (m, 1H), 2.84 (s, 6H), 2.83-2.63 (m, 2H), 2.06-1.85 (m, 2H), 1.49-1.18 (m, 3H)。

EXAMPLE 116 Compound 47 (1- [4- [ amino (4, 5-dichloro-2-hydroxyphenyl) methyl ] piperidin-1-yl ] -2-hydroxyethan-1-one)

Step a:

to a stirred solution of HATU (0.27 g, 0.72 mmol) and 2-hydroxyacetic acid (54 mg, 0.72 mmol) in DMF (4 mL) was added dropwise at room temperature under a nitrogen atmosphereN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide (0.10 g, 0.24 mmol) in DMF (1 mL) and Et₃Solution in N (72 mg, 0.72 mmol). The reaction solution was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction solution was quenched with water (30 mL) at room temperature. The aqueous layer was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash with a solution of 10 mmol/L NH₄HCO₃Eluting with 50% ACN aqueous solution to obtain a light yellow oilN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (2-Hydroxyacetyl) piperidin-4-yl group]Methyl radical]-2-methylpropane-2-sulfinamide (60 mg, 53%): C₂₁H₃₀Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 477, 479 (3: 2), found 477, 479 (3: 2).

Step b:

under nitrogen atmosphere at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (2-Hydroxyacetyl) piperidin-4-yl group]Methyl radical]-2-methylpropaneAlkane-2-sulfinamide (60 mg, 0.13 mmol) and Pd (PPh)₃)₄(3 mg, 0.003 mmol) to a mixture in THF (3 mL) was added NaBH₄(5 mg, 0.13 mmol). The mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction mixture was quenched with water (10 mL). The aqueous layer was extracted with EA (3X 20 mL). The combined organic layers were washed with water (2X 20 mL) and dried over anhydrous Na₂SO₄Dried and filtered. Concentrating the filtrate under reduced pressure to obtain crude productN- ((4, 5-dichloro-2-hydroxyphenyl) (1- (2-hydroxyacetyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide. The crude product was used without further purification in the subsequent step: c ₁₈H₂₆Cl₂N₂O₄S [M + H]⁺Lcms (esi) calculated value of (a): 437, 439 (3: 2), found 437, 439 (3: 2).

Step c:

at room temperature toN- [ (4, 5-dichloro-2-hydroxyphenyl) [1- (2-hydroxyacetyl) piperidin-4-yl]Methyl radical](iii) -2-methylpropane-2-sulfinamide (0.10 g, 0.23 mmol) in 1, 4-dioxane (3 mL) to which was added aqueous HCl (6)N3 mL). The reaction solution was stirred at room temperature for 2 hours. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase A: having a NH concentration of 20 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 23% B to 50% B in 6.5 minutes; a detector: UV 254/210 nm; retention time: 5.67 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 47 (1- [4- [ amino (4, 5-dichloro-2-hydroxyphenyl) methyl ] as a yellow solid]Piperidin-1-yl radical]-2-hydroxyethan-1-one) (20 mg, 13%): C₁₄H₁₈Cl₂N₂O₃ [M + H]⁺Calculated lcms (esi): 333, 335 (3: 2), found 333, 335 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 6.89 (s, 1H), 4.57 (dd, J = 38.8 Hz, 12.8 Hz, 1H), 4.27-4.19 (m, 2H), 3.92 (t, J = 8.0 Hz, 1H), 3.72 (dd, J = 38.8 Hz, 12.8 Hz, 1H), 3.05-2.91 (m, 1H), 2.71-2.57 (m, 1H), 2.15-1.90 (m, 2H), 1.50-1.15 (m, 3H)。

EXAMPLE 117 Compound 48 (1- (4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidine-1-carbonyl) cyclopropanecarbonitrile trifluoroacetic acid)

A, step a:

to a stirred solution of HATU (0.42 g, 1.09 mmol) and 1-cyanocyclopropane-1-carboxylic acid (48 mg, 0.43 mmol) in DMF (3 mL) at room temperature under a nitrogen atmosphere was added Et₃N (43 mg, 0.43 mmol) andN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]-a solution of 2-methylpropane-2-sulfinamide (90 mg, 0.21 mmol) in DMF (2 mL). The reaction solution was stirred at room temperature under nitrogen atmosphere for 1 hour. After stirring at room temperature for an additional 2 hours, the reaction solution was quenched with water (20 mL) at room temperature and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with a solution containing 10 mmol/L NH₄HCO₃Eluting with 30% -70% ACN water solution to obtain yellow oilN- ([1- [ (1-cyanocyclopropyl) carbonyl ] carbonyl]Piperidin-4-yl radical][4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl) -2-methylpropane-2-sulfinamide (0.10 g, 82%): C₂₄H₃₁Cl₂N₃O₃S [M + H]⁺Calculated lcms (esi): 512, 514 (3: 2), found 512, 514 (3: 2).

Step b:

under nitrogen atmosphere at room temperature with stirringN- ([1- [ (1-cyanocyclopropyl) carbonyl ] carbonyl ]Piperidin-4-yl][4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl) -2-methylpropane-2-sulfinamide (0.10 g, 0.20 mmol) and Pd (PPh)₃)₄(5 mg, 0.02 mmol) in THF (3 mL) was added NaBH in portions₄(15 mg, 0.39 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The resulting mixture was quenched with water (20 mL),extracted with EA (3X 20 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. Filtering, and concentrating the filtrate under reduced pressure to obtainN- ((1- (1-cyanocyclopropanecarbonyl) piperidin-4-yl) (4, 5-dichloro-2-hydroxyphenyl) methyl) -2-methylpropane-2-sulfinamide. The crude product was used without further purification in the subsequent step: c₂₁H₂₇Cl₂N₃O₃S [M + H]⁺Calculated lcms (esi): 472, 474 (3: 2), found 472, 474 (3: 2).

Step c:

at room temperature with stirringNTo a solution of (- ((1- (1-cyanocyclopropanecarbonyl) piperidin-4-yl) (4, 5-dichloro-2-hydroxyphenyl) methyl) -2-methylpropane-2-sulfinamide (crude) in 1, 4-dioxane (2 mL) was added aqueous HCl (6 mL)N1.5 mL). The reaction solution was stirred at room temperature for 2 hours. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column, 100A, 10 μm, 19 mm × 250 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 18% B to 68% B in 7 minutes; a detector: UV 254/210 nm; retention time: 5.20 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 48 (1- (4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidine-1-carbonyl) cyclopropanecarbonitrile trifluoroacetic acid) (28.4 mg, 53% two steps total) C as an off-white solid ₁₇H₁₉Cl₂N₃O₂ [M + H]⁺Calculated lcms (esi): 368, 370 (3: 2), found 368, 370 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.45 (s, 1H), 7.09 (s, 1H), 4.54 (d, J = 14.0 Hz, 1H), 4.40 (d, J = 13.8 Hz, 1H), 4.19 (d, J = 9.9 Hz, 1H), 3.30-3.02 (m, 1H), 2.95-2.58 (m, 1H), 2.51-2.38 (m, 1H), 2.14-2.01 (m, 1H), 1.58 (s, 4H), 1.50-1.28 (m, 3H)； ¹⁹F-NMR (376 MHz, CD₃OD) δ -77.03.

EXAMPLE 118 Compound 49 (1- (4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) -3-hydroxy-3-methylbutan-1-one trifluoroacetic acid)

Step a:

to a stirred solution of HATU (0.49 g, 1.29 mmol) and 3-hydroxy-3-methylbutyric acid (0.10 g, 0.86 mmol) in DMF (3 mL) at room temperature under a nitrogen atmosphere was added Et₃N (0.86 g, 0.86 mmol) andN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]-solution of 2-methylpropane-2-sulfinamide (0.18 g, 0.43 mmol) in DMF (2 mL). After stirring at room temperature for an additional 2 hours, the reaction solution was quenched with water (20 mL) at room temperature and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purifying the residue by reverse phase chromatography, eluting with 50% -80% aqueous ACN (plus 0.05% TFA) to obtain a red solidN- ((2- (allyloxy) -4, 5-dichlorophenyl) (1- (3-hydroxy-3-methylbutyryl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (0.14 g, 54%): C₂₄H₃₆Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 519, 521 (3: 2), found 519, 521 (3: 2).

Step b:

under nitrogen atmosphere at room temperature with stirringN- ((2- (allyloxy) -4, 5-dichlorophenyl) (1- (3-hydroxy-3-methylbutyryl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (0.14, 0.27 mmol) and Pd (PPh)₃)₄(34 mg, 0.03 mmol) in THF (5 mL) NaBH was added₄(16 mg, 0.41 mmol). The mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction mixture was quenched with water (30 mL) and extracted with EA (3X 30 mL). The combined organic layers were washed with water (2X 20 mL) and dried over anhydrous Na₂SO₄Dried and filtered. Concentrating the filtrate under reduced pressure to obtain crude productN-((4, 5-dichloro-2-hydroxyphenyl) (1- (3-hydroxy-3-methylbutyryl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide. The crude product was taken without further purificationFor the subsequent steps: c₂₁H₃₂Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 479, 481 (3: 2), found 479, 481 (3: 2).

Step c:

at room temperature toN-(4, 5-dichloro-2-hydroxyphenyl) (1- (3-hydroxy-3-methylbutyryl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (crude) solution in 1, 4-dioxane (3 mL) was added aqueous HCl (6 mL)N3 mL). The reaction solution was stirred at room temperature for 2 hours. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column, 100A, 10 μm, 19 mm × 250 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 5% B to 50% B in 7 minutes; a detector: UV 254/210 nm; retention time: 6.28 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 49 (1- (4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) -3-hydroxy l-3-methylbutan-1-one trifluoroacetic acid) (37 mg, 49% two-step total) C as an off-white solid ₁₇H₂₄Cl₂N₂O₃ [M + H]⁺Lcms (esi) calculated value of (a): 375, 377 (3: 2), found 375, 377 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.44 (d, J = 1.5 Hz, 1H), 7.09 (s, 1H), 4.66 (dd, J = 54.9, 13.4 Hz, 1H), 4.25-4.03 (m, 2H), 3.20-2.96 (m, 1H), 2.75-2.53 (m, 3H), 2.47-2.33 (m, 1H), 2.01 (d, J = 12.8 Hz, 1H), 1.47-1.12 (m, 9H)； ¹⁹F-NMR (376 MHz, CD₃OD) δ -77.00.

example 119. Compound 50 ((2)S) -2-amino-1- (4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) propan-1-one trifluoroacetic acid)

Step a:

stirring under nitrogen atmosphere at room temperatureS) -2- ((tert-butoxycarbonyl) amino) propaneAcid (0.20 g, 1.06 mmol) and N- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]Et was added to a solution of (2-methylpropane-2-sulfinamide) (0.44 g, 1.06 mmol) in DMF (5 mL)₃N (0.32 g, 3.18 mmol) and EDCI (0.61 g, 3.18 mmol). The reaction solution was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction solution was quenched with water (30 mL) at room temperature and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (9/1) to give ((2) as a yellow solidS) -tert-butyl 1- (4- ((2- (allyloxy) -4, 5-dichlorophenyl) (1, 1-dimethylethylenesulfonamido) methyl) piperidin-1-yl) -1-oxopropan-2-yl) carbamate (0.15 g, 42%)₂₇H₄₁Cl₂N₃O₅S [M + H]⁺Calculated lcms (esi): 590, 592 (3: 2), found 590, 592 (3: 2).

Step b:

stirring in nitrogen atmosphere at room temperatureS) Tert-butyl (1- (4- ((2- (allyloxy) -4, 5-dichlorophenyl) (1, 1-dimethylethylenesulfonamido) methyl) piperidin-1-yl) -1-oxopropan-2-yl) carbamate (100 mg, 0.17 mmol) and Pd (PPh)₃)₄(4 mg, 0.002 mmol) in THF (3 mL) NaBH was added₄(16 mg, 0.34 mmol). The mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction mixture was quenched with water (10 mL). The aqueous layer was extracted with EA (3X 20 mL). The combined organic layers were washed with water (2X 20 mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure to give a crude ((2)S) -tert-butyl 1- (4- ((4, 5-dichloro-2-hydroxyphenyl) (1, 1-dimethylethylenesulfonamido) methyl) piperidin-1-yl) -1-oxopropan-2-yl) carbamate. The crude product was used without further purification in the subsequent step: c₂₄H₃₇Cl₂N₃O₅S [M + H]⁺Calculated lcms (esi): 550, 552 (3: 2), found 550, 552 (3: 2).

Step c:

at room temperature to ((2)S) (iv) -1- (4- ((4, 5-dichloro-2-hydroxyphenyl) (1, 1-dimethylethylenesulfonamido) methyl) piperidin-1-yl) -1-oxopropan-2-yl) carbamic acid tert-butyl ester (crude) to a solution in 1, 4-dioxane (3 mL) was added aqueous HCl (6. mu.l) N3 mL). The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was dissolved in DCM (6 mL), and TFA (3 mL) was added at room temperature. The reaction solution was stirred at room temperature for an additional 1 hour. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column, 100A, 10 μm, 19 mm s 250 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 5% B to 42% B in 6.5 minutes; a detector: UV 254/210 nm; retention time: 5.80 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 50 ((2) as a yellow solidS) -2-amino-1- (4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) propan-1-one trifluoroacetic acid) (47.2 mg, 53% two-step total) C₁₅H₂₁Cl₂N₃O₂ [M + H]⁺Calculated lcms (esi): 346, 348 (3: 2), found 346, 348 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.44 (d, J = 7.2 Hz, 1H), 7.09 (s, 1H), 4.56 (dd, J = 38.8 Hz, 12.8 Hz, 1H), 4.45-4.36 (m, 1H), 4.26-4.13 (m, 1H), 3.92 (dd, J = 38.8 Hz, 12.8 Hz, 1H), 3.25-3.01 (m, 1H), 2.85-2.57 (m, 1H), 2.52-2.32 (m, 1H), 2.15-2.01 (m, 1H), 1.46 (d, J = 12.8 Hz, 3H), 1.44-1.05 (m, 3H)； ¹⁹F-NMR (282 MHz, CD₃OD) δ -76.93.

EXAMPLE 120 Compound 51 (2- [ amino [1- (cyclopropylmethyl) piperidin-4-yl ] methyl ] -4, 5-dichlorophenol trifluoroacetic acid)

Step a:

under nitrogen atmosphere at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzeneBase of](piperidin-4-yl) methyl ]-2-methylpropane-2-sulfinamide (0.20 g, 0.48 mmol) and cyclopropanecarboxaldehyde (50 mg, 0.71 mmol) in MeOH (4 mL) was added AcOH (29 mg, 0.48 mmol) and NaBH (OAc)₃(0.30 g, 1.43 mmo). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The resulting mixture was quenched with water (20 mL) at room temperature and extracted with EA (3X 40 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with a solution containing 10 mmol/L NH₄HCO₃Eluted with 70% aqueous MeOH to give a yellow oilN- [ [1- (cyclopropylmethyl) piperidin-4-yl group][4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]2-methylpropane-2-sulfinamide (0.17g, 75%): C₂₃H₃₄Cl₂N₂O₂S [M + H]⁺Calculated lcms (esi): 473, 475 (3: 2), found 473, 475 (3: 2).

Step b:

under nitrogen atmosphere at room temperature with stirringN- [ [1- (cyclopropylmethyl) piperidin-4-yl group][4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]-2-methylpropane-2-sulfinamide (0.17g, 0.36 mmol) and Pd (PPh)₃)₄(8 mg, 0.01 mmol) in THF (4 mL) NaBH was added₄(20 mg, 0.54 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. The resulting mixture was quenched with water (30 mL) at room temperature. The aqueous layer was extracted with EA (3X 20 mL). The combined organic layers were washed with water (2X 20 mL) and dried over anhydrous Na ₂SO₄Dried and filtered. Concentrating the filtrate under reduced pressure to obtain crude productN- ((1- (cyclopropylmethyl) piperidin-4-yl) (4, 5-dichloro-2-hydroxyphenyl) methyl) -2-methylpropane-2-sulfinamide. The crude product was used without further purification in the subsequent step: c₂₀H₃₀Cl₂N₂O₂S [M + H]⁺Calculated lcms (esi): 433, 435 (3: 2), found 433, 435 (3: 2).

Step c:

at room temperature with stirringN- [ [1- (Ring)Propylmethyl) piperidin-4-yl](4, 5-dichloro-2-hydroxyphenyl) methyl group](iii) -2-methylpropane-2-sulfinamide (0.12 g, 0.28 mmol) in 1, 4-dioxane (3 mL) to which was added aqueous HCl (6)N1 mL). The reaction solution was stirred at room temperature for 2 hours. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 33% B to 50% B in 6.5 minutes; a detector: UV 254/210 nm; retention time: 5.86 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 51 (2- [ amino [1- (cyclopropylmethyl) piperidin-4-yl) as an off-white solid]Methyl radical]-4, 5-dichlorophenol trifluoroacetic acid) (18 mg, 19% of two steps in total): C ₁₆H₂₂Cl₂N₂O [M + H]⁺Calculated lcms (esi): 329, 331 (3: 2), found 329, 331 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.48 (s, 1H), 7.11 (s, 1H), 4.26 (d, J = 9.5 Hz, 1H), 3.79 (d, J = 12.6 Hz, 1H), 3.66 (d, J = 12.6 Hz, 1H), 3.10-2.87 (m, 4H), 2.53-2.36 (m, 1H), 2.25 (d, J = 14.2 Hz, 1H), 1.80-1.49 (m, 3H), 1.20-1.03 (m, 1H), 0.86-0.71 (m, 2H), 0.50-0.30 (m, 2H)。

EXAMPLE 121 Compound 52 (2- [ amino (azetidin-3-yl) methyl ] -4, 5-dichlorophenol trifluoroacetic acid)

Step a:

to a stirred solution of 1-bromo-4, 5-dichloro-2- (prop-2-en-1-yloxy) benzene (example 6, step b) (2.40 g, 8.60 mmol) in THF (20 mL) at 0 deg.C under a nitrogen atmosphere was added dropwisei-PrMgCl (5.73 mL, 11.46 mmol, 2M in THF). The reaction was stirred at 0 ℃ for 30 minutes. Then 3- [ methoxy (methyl) carbamoyl group]Tert-butyl azetidine-1-carboxylate (1.40 g, 5.73 mmol) was added to the reaction. The reaction was stirred at 0 ℃ for an additional 1.5 hours. Reacting with saturated NH₄Aqueous Cl (5 mL) was quenched and diluted with EA (50 mL) and water (30 mL). The aqueous layer was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography, eluting with PE/EA (4/1), and obtaining 3- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] in the form of pale yellow oil]Carbonyl radical]Azetidine-1-carboxylic acid tert-butyl ester (1.30 g, 53%): C₁₈H₂₁Cl₂NO₄ [M + Na]⁺Calculated lcms (esi): 408, 410 (3: 2), found 408, 410 (3: 2); ¹H NMR (400 MHz, CD₃OD) δ 7.90 (s, 1H), 7.37 (s, 1H), 6.28-6.06 (m, 1H), 5.56-5.36 (m, 2H), 4.74 (d, J = 5.8, Hz, 2H), 4.19-4.00 (m, 5H), 1.46 (s, 9H)。

Step b:

to a stirred 3- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl group at room temperature under a nitrogen atmosphere]Carbonyl radical]To a solution of azetidine-1-carboxylic acid tert-butyl ester (0.50 g, 1.29 mmol) and tert-butanesulfinamide (0.47 g, 3.88 mmol) in THF (8 mL) was added Ti (OEt)₄(2.36 g, 10.36 mmol). The reaction was stirred at 70 ℃ for 16 hours. The reaction was saturated with Na₂CO₃Aqueous solution (30 mL) was quenched. The resulting mixture was filtered through celite (celite), the filtrate was diluted with EA (30 mL) and water (30 mL), and the aqueous layer was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography, eluting with PE/EA (5/1), and obtaining 3- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] as yellow oil][ (2-methylpropane-2-sulfinyl) imino]Methyl radical]Azetidine-1-carboxylic acid tert-butyl ester (0.49 g, 70%): C₂₂H₃₀Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 489, 491 (3: 2), found 489, 491 (3: 2).

Step c:

to a stirred 3- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl group at room temperature][ (2-methylpropane-2-sulfinyl) eneAmino group]Methyl radical]To a solution of azetidine-1-carboxylic acid tert-butyl ester (0.49 g, 1.00 mmol) in MeOH (5 mL) was added NaBH ₄(76 mg, 2.00 mmol). Saturated NH is used for reaction₄Aqueous Cl (2 mL) was quenched and diluted with EA (30 mL) and water (30 mL). The aqueous layer was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 3- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] as a pale yellow solid][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]Azetidine-1-carboxylic acid tert-butyl ester (0.50 g, crude), which was used in the next step without further purification: c₂₂H₃₂Cl₂N₂O₄S [M + Na]⁺Calculated lcms (esi): 513, 515 (3: 2), found 513, 515 (3: 2).

Step d:

to a stirred 3- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl group at room temperature][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]Azetidine-1-carboxylic acid tert-butyl ester (0.50 g, 1.02 mmol) and Pd (PPh)₃)₄(59 mg, 0.05 mmol) in THF (5 mL) NaBH was added₄(77 mg, 2.03 mmol). The reaction was stirred at room temperature for 1 hour. Reacting with saturated NH₄Aqueous Cl (30 mL) was quenched. The resulting mixture was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE/EA (5/1) to give 3- [ (4, 5-dichloro-2-hydroxyphenyl) [ (2-methylpropane-2-sulfinyl) amino ]Methyl radical]Azetidine-1-carboxylic acid tert-butyl ester (0.30 g, 65% in two steps) C₁₉H₂₈Cl₂N₂O₄S [M + Na]⁺Lcms (esi) calculated value of (a): 473, 475 (3: 2), found 473, 475 (3: 2).

Step e:

to a stirred mixture of 3- [ (4, 5-dichloro-2-hydroxyphenyl) [ (2-methylpropane-2-sulfinyl) amino group at room temperature]Methyl radical]A solution of azetidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.44 mmol) in 1, 4-dioxane (4 mL)Adding aqueous HCl (4)N2 mL). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The mixture was then dissolved in DCM (2 mL) and TFA (0.5 mL) was added at room temperature. The resulting solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 6% B to 18% B in 9 minutes; a detector: UV 254/210 nm; retention time: 6.80 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 52 (2- [ amino (azetidin-3-yl) methyl) as a violet oil]-4, 5-dichlorophenol trifluoroacetic acid) (44.7 mg, 28%): C ₁₀H₁₂Cl₂N₂O [M + H]⁺Lcms (esi) calculated value of (a): 247, 249 (3: 2), found 247, 249 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.52 (d, J = 1.6 Hz, 1H), 7.13 (s, 1H), 4.83 (d, J = 9.7 Hz, 1H), 4.31-4.13 (m, 2H), 4.03-3.91 (m, 1H), 3.90-3.69 (m, 2H)； ¹⁹F NMR (282 MHz, CD₃OD) δ -77.11.

EXAMPLE 122 Compound 53 (4- [ amino (4, 5-dichloro-2-hydroxyphenyl) methyl ] piperidine-1-carboxamide)

Step a:

under nitrogen atmosphere at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.20 g, 0.48 mmol) and Et₃A solution of N (72 mg, 0.72 mmol) in DCM (3 mL) was added isocyanatotrimethylsilane (66 mg, 0.57 mmol) dropwise. The resulting solution was quenched with water (30 mL) at room temperature and extracted with EA (3X 50 mL) under nitrogen at room temperature for 2 h of stirring. The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. Filtering, concentrating the filtrate under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 45% aqueous ACN (plus 0.05% TFA) to give 4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] as a colorless oil][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]Piperidine-1-carboxamide (0.15 g, 68%): C₂₀H₂₉Cl₂N₃O₃S [M + H]⁺Calculated lcms (esi): 462, 464 (3: 2), found 462, 464 (3: 2).

Step b:

to a stirred 4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl group at room temperature under a nitrogen atmosphere ][ (2-methylpropane-2-sulfinyl) amino group]Methyl radical]Piperidine-1-carboxamide (0.15 g, 0.33 mmol) and Pd (PPh)₃)₄(8 mg, 0.01 mmol) in THF (5 mL) NaBH was added₄(18 mg, 0.50 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The resulting mixture was quenched with water (2 mL) at room temperature and concentrated under reduced pressure to give 4- ((4, 5-dichloro-2-hydroxyphenyl) (1, 1-dimethylethylenesulfonamido) methyl) piperidine-1-carboxamide. The residue was used without further purification in the next step: c₁₇H₂₅Cl₂N₃O₃S [M + H]⁺Calculated lcms (esi): 422, 424 (3: 2), found 422, 424 (3: 2).

Step c:

to a stirred mixture of 4- ((4, 5-dichloro-2-hydroxyphenyl) (1, 1-dimethylethylenesulfonamido) methyl) piperidine-1-carboxamide (crude) in 1, 4-dioxane (3 mL) was added aqueous HCl (6 mL) at room temperatureN1 mL). After stirring at room temperature for 2 hours, the resulting solution was taken up in saturated NaHCO₃The aqueous solution was neutralized to pH 7 and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase A: having a NH concentration of 20 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 5% B to 90% B in 8 minutes; a detector: UV 254/210 nm; retention time: 6.75 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 53 (4- [ amino (4, 5-dichloro-2-hydroxybenzene) as an off-white solid Radical) methyl]Piperidine-1-carboxamide) (69.6 mg, 71% two steps total): C₁₃H₁₇Cl₂N₃O₂ [M + H]⁺Lcms (esi) calculated value of (a): 318, 320 (3: 2), found 318, 320 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.20 (s, 1H), 6.86 (s, 1H), 4.11 (d, J = 13.5 Hz, 1H), 3.96 (d, J = 13.7 Hz, 1H), 3.88 (d, J = 7.6 Hz, 1H), 2.85-2.62 (m, 2H), 2.04-1.86 (m, 2H), 1.50-1.09 (m, 3H)。

example 123 Compound 54 ((2)R) -2-amino-1- (4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) propan-1-one trifluoroacetic acid)

Step a:

stirring under nitrogen atmosphere at room temperatureR) -2- ((tert-butoxycarbonyl) amino) propanoic acid (0.20 g, 1.06 mmol) and N- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]Et was added to a solution of (2-methylpropane-2-sulfinamide) (0.44 g, 1.06 mmol) in DMF (5 mL)₃N (0.32 g, 3.18 mmol) and EDCI (0.61 g, 3.18 mmol). The reaction solution was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction solution was quenched with water (30 mL) at room temperature and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (9/1) to give ((2) as a yellow solidR) -tert-butyl 1- (4- ((2- (allyloxy) -4, 5-dichlorophenyl) (1, 1-dimethylethylenesulfonamido) methyl) piperidin-1-yl) -1-oxopropan-2-yl) carbamate (0.10 g, 36%) ₂₇H₄₁Cl₂N₃O₅S [M + H]⁺Calculated lcms (esi): 590, 592 (3: 2), found 590, 592 (3: 2).

Step b:

stirred ((2) at room temperature under nitrogen atmosphereR) -1- (4- ((2- (allyloxy) s)) -4, 5-dichlorophenyl) (1, 1-dimethylethylenesulfonamido) methyl) piperidin-1-yl) -1-oxopropan-2-yl) carbamic acid tert-butyl ester (0.10 g, 0.17 mmol) and Pd (PPh)₃)₄(4 mg, 0.002 mmol) in THF (3 mL) NaBH was added₄(16 mg, 0.34 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. The resulting mixture was quenched with water (10 mL). The aqueous layer was extracted with EA (3X 20 mL). The combined organic layers were washed with water (2X 20 mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure to give crude (((2)R) -tert-butyl 1- (4- ((4, 5-dichloro-2-hydroxyphenyl) (1, 1-dimethylethylenesulfonamido) methyl) piperidin-1-yl) -1-oxopropan-2-yl) carbamate. The crude product was used without further purification in the subsequent step: c₂₄H₃₇Cl₂N₃O₅S [M + H]⁺Calculated lcms (esi): 550, 552 (3: 2), found 550, 552 (3: 2).

Step c:

at room temperature to ((2)R) (iv) -1- (4- ((4, 5-dichloro-2-hydroxyphenyl) (1, 1-dimethylethylenesulfonamido) methyl) piperidin-1-yl) -1-oxopropan-2-yl) carbamic acid tert-butyl ester (crude) to a solution in 1, 4-dioxane (3 mL) was added aqueous HCl (6. mu.l) N3 mL). The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was dissolved in DCM (6 mL), and TFA (3 mL) was added at room temperature. The reaction solution was stirred at room temperature for another 1 hour. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column, 100A, 10 μm, 19 mm × 250 mm; mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 5% B to 42% B in 6.5 minutes; a detector: UV 254/210 nm; retention time: 5.80 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure, and compound 54 ((2) was obtained as a yellow solidR) -2-amino-1- (4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) propan-1-one trifluoroacetic acid) (34.5 mg, 48% two-step total) C₁₅H₂₁Cl₂N₃O₂ [M + H]⁺Calculated lcms (esi): 346, 348 (3: 2), found 346, 348 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.44 (s, 1H), 7.09 (s, 1H), 4.56 (dd, J = 38.8 Hz, 12.8 Hz, 1H), 4.45-4.36 (m, 1H), 4.26-4.13 (m, 1H), 3.91 (dd, J = 38.8 Hz, 12.8 Hz, 1H), 3.25-3.01 (m, 1H), 2.83-2.57 (m, 1H), 2.50-2.29 (m, 1H), 2.17-1.99 (m, 1H), 1.41 (d, J = 12.8 Hz, 3H), 1.52-1.10 (m, 3H)； ¹⁹F-NMR (282 MHz, CD₃OD) δ -76.92.

EXAMPLE 124 (2- [4- [ amino (4, 5-dichloro-2-hydroxyphenyl) methyl)]Piperidin-1-yl radical]-N,N-dimethylacetamide)

Step a:

under nitrogen atmosphere at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl ]2-Bromopropane-2-sulfinamide (0.10 g, 0.24 mmol) and DIEA (62 mg, 0.48 mmol) in DCM (3 mL) were addedN,N-dimethylacetamide (48 mg, 0.29 mmol). The reaction solution was stirred at room temperature under nitrogen atmosphere for 2 hours. The resulting solution was concentrated under reduced pressure. The residue was purified by washing with a solution having a concentration of 10 mmol/L NH₄HCO₃Purifying by reverse phase chromatography with 80% ACN aqueous solution to obtain 2- (4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl) as yellow oil][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]Piperidin-1-yl) -substituted acidsN,N-dimethylacetamide (50 mg, 42%): C₂₃H₃₅Cl₂N₃O₃S [M + H]⁺Calculated lcms (esi): 504, 506 (3: 2), found 504, 506 (3: 2).

Step b:

to a stirred 2- (4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl group at room temperature under a nitrogen atmosphere][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]Piperidin-1-yl) -N,NDimethylacetamide (50 mg, 0.10 mmol) and Pd (PPh)₃)₄ (3 mg, 0.002 mmol) in THF (4 mL) NaBH was added₄(5 mg, 0.12 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. The resulting mixture was quenched with water (30 mL) at room temperature and extracted with EA (3X 20 mL). The combined organic layers were washed with water (2X 20 mL) and dried over anhydrous Na ₂SO₄Dried and filtered. Concentrating the filtrate under reduced pressure to obtain crude 2- (4- ((4, 5-dichloro-2-hydroxyphenyl) (1, 1-dimethylethylenesulfonamido) methyl) piperidin-1-yl) -propanoic acidN,N-dimethylacetamide. The crude product was used without further purification in the subsequent step: c₂₀H₃₁Cl₂N₃O₃S [M + H]⁺Calculated lcms (esi): 464, 466 (3: 2), found 464, 466 (3: 2).

Step c:

to stirred 2- (4- ((4, 5-dichloro-2-hydroxyphenyl) (1, 1-dimethylethylenesulfonamido) methyl) piperidin-1-yl) -N,N-Dimethylacetamide (50 mg, 0.11 mmol) in 1, 4-dioxane (3 mL) to a mixture of HCl in water (6 mL)N1 mL). The reaction solution was stirred at room temperature for 2 hours. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase A: having a NH concentration of 20 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 5% B to 60% B in 6.5 minutes; a detector: UV 254/210 nm; retention time: 5.38 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 55 (2- [4- [ amino (4, 5-dichloro-2-hydroxyphenyl) methyl) as a colorless oil ]Piperidin-1-yl radical]-N,NDimethylacetamide) (18 mg, 46% of two-stage sum): C₁₆H₂₃Cl₂N₃O₂ [M + H]⁺Calculated lcms (esi): 360, 362 (3: 2), found 360, 362 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.18 (s, 1H), 6.84 (s, 1H), 3.88 (d, J = 7.8 Hz, 1H), 3.20 (s, 2H), 3.09 (s, 2H), 3.03 (d, J = 11.8 Hz, 1H), 2.94 (s, 3H), 2.94-2.85 (m, 2H), 2.16-1.96 (m, 2H), 1.94-1.71 (m, 2H), 1.48-1.32 (m, 3H)。

EXAMPLE 125 Compound 56 (2- [ amino [1- (2-hydroxy-2-methylpropyl) piperidin-4-yl ] methyl ] -4, 5-dichlorophenol trifluoroacetic acid)

Step a:

under nitrogen atmosphere at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]To a mixture of-2-methylpropane-2-sulfinamide (0.20 g, 0.48 mmol) and methyl 2-bromoacetate (0.11 g, 0.72 mmol) in ACN (5 mL) was added DIEA (0.12 g, 0.95 mmol). After stirring at room temperature for 16 hours under a nitrogen atmosphere, the resulting solution was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with a solution containing 10 mmol/L NH₄HCO₃Eluting with 80% aqueous solution of ACN to obtain 2- (4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl) in the form of yellow oil][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]Piperidin-1-yl) acetic acid methyl ester (0.18 g, 77%): C₂₂H₃₂Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 491, 493 (3: 2), found 491, 493 (3: 2).

Step b:

to a stirred 2- (4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl group at room temperature under a nitrogen atmosphere][ (2-methylpropane-2-sulfinyl) amino ]Methyl radical]Piperidin-1-yl) acetic acid methyl ester (0.18 g, 0.37 mmol) and Pd (PPh)₃)₄(9 mg, 0.01 mmol) to a mixture in THF (3 mL) NaBH was added₄(17 mg, 0.44 mmol). The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with water (30 mL) at room temperature and extracted with EA (3X 20 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give methyl 2- (4- ((4, 5-dichloro-2-hydroxyphenyl) (1, 1-dimethylethylenesulfonamido) methyl) piperidin-1-yl) acetate. The crude product was used without further purification in the subsequent step: c₁₉H₂₈Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 451, 452 (3: 2), found 451, 452 (3: 2).

Step c:

to a stirred solution of methyl 2- (4- ((4, 5-dichloro-2-hydroxyphenyl) (1, 1-dimethylethylenesulfonamido) methyl) piperidin-1-yl) acetate (crude) in 1, 4-dioxane (5 mL) was added aqueous HCl (4, 5-dichloro-2-hydroxyphenyl) at room temperatureN1 mL). The reaction solution was stirred at room temperature for 2 hours. The resulting solution was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with a solution containing 10 mmol/L NH₄HCO₃Eluting with 50% aqueous solution of ACN to obtain 2- [4- [ amino (4, 5-dichloro-2-hydroxyphenyl) methyl ] in the form of pale yellow oil ]Piperidin-1-yl]Methyl acetate (0.10 g, 80% of the two steps total): C₁₅H₂₀Cl₂N₂O₃ [M + H]⁺Calculated lcms (esi): 347, 349 (3: 2), found 347, 349 (3: 2).

Step d:

to a stirred solution of 2- [4- [ amino (4, 5-dichloro-2-hydroxyphenyl) methyl group at room temperature under a nitrogen atmosphere]Piperidin-1-yl radical]To a solution of methyl acetate (80 mg, 0.23 mmol) in THF (3 mL) was added MeMgBr (0.27 g, 2.30 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The resulting mixture was quenched with water (30 mL) at room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: sunfire Prep C₁₈OBD column, 10 μm, 19X 250 mm; mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 5% B to 45% B in 6 minutes; a detector: UV 220/254 nm; retention time: for 5 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure, and compound 56 (2- [ amino [1- (2-hydroxy-2-methylpropyl) piperidin-4-yl) was obtained as an off-white solid]Methyl radical]-4, 5-dichlorophenol trifluoroacetic acid) (15 mg, 19%): C₁₆H₂₄Cl₂N₂O₂ [M + H]⁺Calculated lcms (esi): 347, 349 (3: 2), found 347, 349 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.47 (s, 1H), 7.09 (s, 1H), 4.24 (d, J = 9.4 Hz, 1H), 3.89 (d, J = 12.9 Hz, 1H), 3.73 (d, J = 12.9 Hz, 1H), 3.29-2.96 (m, 4H), 2.55-2.30 (m, 1H), 2.26-2.09 (m, 1H), 1.95-1.48 (m, 3H), 1.35 (s, 6H)。

EXAMPLE 126 Compound 57 (4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) - N-cyclopropylpiperidine-1-carboxamide)

A, step a:

stirred mixture of CDI (0.21 g, 1.29 mmol) and Et at 0 deg.C₃N (0.26 g, 2.58 mmol) in THF (5 mL) was added portionwiseN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.18 g, 0.43 mmol). After stirring at 0 ℃ for 1 hour, cyclopropylamine (73.5 mg, 1.29 mmol) was added to the resulting solution at 0 ℃. The reaction solution was allowed to warm to room temperature and stirred for an additional 1 hour. The resulting solution was quenched with water (30 mL) at room temperature and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with a solution containing 10 mmol/L NH₄HCO₃Is eluted in 70% aqueous ACN and is obtained in the form of a yellow oilN-cyclopropyl-4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]Piperidine-1-carboxamide (0.17 g, 70%): C₂₃H₃₃Cl₂N₃O₃S [M + H]⁺Calculated lcms (esi): 502, 504 (3: 2), found 502, 504 (3: 2).

Step b:

under nitrogen atmosphere at room temperature with stirringN-cyclopropyl-4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]Piperidine-1-carboxamide (0.17 g, 0.34 mmol) and Pd (PPh)₃)₄(38 mg, 0.03 mmol) in THF (5 mL) NaBH was added portionwise₄(19 mg, 0.65 mmol). The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with water (30 mL) at room temperature and extracted with EA (3X 20 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. Filtering, and concentrating the filtrate under reduced pressure to obtainN-cyclopropyl-4- ((4, 5-dichloro-2-hydroxyphenyl) (1, 1-dimethylethylenesulfonamido) methyl) piperidine-1-carboxamide. The crude product was used without further purification in the subsequent step: c₂₀H₂₉Cl₂N₃O₃S [M + H]⁺Calculated lcms (esi): 462, 464 (3: 2), found 462, 464 (3: 2).

Step c:

at room temperature with stirringN-cyclopropyl-4- ((4, 5-dichloro-2-hydroxyphenyl) (1, 1-dimethylethylenesulfonamido) methyl) piperidine-1-carboxamide (crude) to a solution in 1, 4-dioxane (4 mL) was added aqueous HCl (6 mL)N2 mL). The reaction solution was stirred at room temperature for 2 hours. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column, 100A, 10 μm, 19 mm × 250 mm; mobile phase A: having a NH concentration of 20 mmol/L ₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 34% B to 46% B in 6.5 minutes; a detector: UV 254/210 nm; retention time: 6.0 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give the compound 57 (4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) -N-Cyclopropylpiperidine-1-carboxamide) (25 mg, 31% of two steps in total): C₁₆H₂₁Cl₂N₃O₂ [M + H]⁺Calculated lcms (esi): 358, 360 (3: 2), found 358, 360 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.21 (s, 1H), 6.86 (s, 1H), 4.09 (d, J = 13.5 Hz, 1H), 3.96 (d, J = 13.3 Hz, 1H), 3.88 (d, J = 7.7 Hz, 1H), 2.78-2.59 (m, 2H), 2.57-2.46 (m, 1H), 2.00-1.86 (m, 2H), 1.40 (d, J = 13.3 Hz, 1H), 1.29-1.08 (m, 2H), 0.70-0.62 (m, 2H), 0.52-0.40 (m, 2H)。

EXAMPLE 127 Compound 58 (2- [ amino ([1- [ (5-methyl-1, 2-oxazol-3-yl) methyl ] piperidin-4-yl) methyl ] -4, 5-dichlorophenol trifluoroacetic acid)

Step a:

under nitrogen atmosphere at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]To a solution of-2-methylpropane-2-sulfinamide (0.20 g, 0.48 mmol) and DIEA (0.12 g, 0.95 mmol) in ACN (8 mL) was added 3- (bromomethyl) -5-methyl-1, 2-oxazole (0.13 g, 0.72 mmol). The reaction solution was stirred at room temperature for 4 hours under a nitrogen atmosphere. The resulting solution was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 65% aqueous ACN (plus 0.05% TFA) to afford the title compound as a pale yellow oil N- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([1- [ (5-methyl-1, 2-oxazol-3-yl) methyl)]Piperidin-4-yl]) Methyl radical]-2-methylpropane-2-sulfinamide (90 mg, 37%): C₂₄H₃₃Cl₂N₃O₃S [M + H]⁺Calculated lcms (esi): 514, 516 (3: 2), found 514, 516 (3: 2).

Step b:

under nitrogen atmosphere at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([1- [ (5-methyl-1, 2-oxazol-3-yl) methyl]Piperidin-4-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide (90 mg, 0.17 mmol) and Pd (PPh)₃)₄(4 mg, 0.003 mmol) in THF (3 mL) NaBH was added₄(7.9 mg, 0.21 mmol, 1.2 equiv.). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. The resulting mixture was quenched with water (30 mL) at room temperature and extracted with EA (3X 20 mL). The combined organic layers were washed with water (2X 20 mL) and dried over anhydrous Na₂SO₄Dried and filtered. Concentrating the filtrate under reduced pressure to obtain crude productN- [ (4, 5-dichloro-2-hydroxyphenyl) ([1- [ (5-methyl-1, 2-oxazol-3-yl) methyl)]Piperidin-4-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide. The crude product was used without further purification in the subsequent step: c₂₁H₂₉Cl₂N₃O₃S [M + H]⁺Calculated lcms (esi): 474, 476 (3: 2), found 474, 476 (3: 2).

Step c:

to be stirredN- [ (4, 5-dichloro-2-hydroxyphenyl) ([1- [ (5-methyl-1, 2-oxazol-3-yl) methyl)]Piperidin-4-yl]) Methyl radical]-2-methylpropane-2-sulfinamide (crude) solution in 1, 4-dioxane (3 mL) aqueous HCl (4) was addedN1 mL). The reaction solution was stirred at room temperature for 2 hours. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase A: having a NH concentration of 10 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 10% B to 50% B in 6.5 minutes; a detector: UV 254/210 nm; retention time: 5.88 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 58 (2- [ amino ([1- [ (5-methyl-1, 2-oxazol-3-yl) methyl) as a brown solid]Piperidin-4-yl radical]) Methyl radical]-4, 5-dichlorophenol trifluoroacetic acid) (9.8 mg, 20% of two steps in total): C₁₇H₂₁Cl₂N₃O₂[M + H]⁺Calculated lcms (esi): 370, 372 (3: 2), found 370, 372 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.46 (s, 1H), 7.10 (s, 1H), 6.32 (s, 1H), 4.36 (s, 2H), 4.26 (d, J = 9.6 Hz, 1H), 3.70 (d, J = 12.5 Hz, 1H), 3.55 (d, J = 12.5 Hz, 1H), 3.23-2.98 (m, 2H), 2.54-2.38 (m, 1H), 2.47 (s, 3H), 2.33-2.19 (m, 1H), 1.86-1.51 (m, 3H)； ¹⁹F NMR (282 MHz, CD₃OD) δ -76.98.

EXAMPLE 128 Compound 59 (2- [ amino (4-fluoropiperidin-4-yl) methyl ] -4, 5-dichlorophenol trifluoroacetic acid)

Step a:

to a stirred mixture of 1-bromo-4, 5-dichloro-2- (prop-2-en-1-yloxy) benzene (example 6, step b) (1.50 g, 5.17 mmol) at 0 ℃ under nitrogen ) To a solution in THF (15 mL) was added dropwisei-PrMgCl (3.44 mL, 6.88 mmol, 2M in THF). The reaction was stirred at 0 ℃ for 30 minutes. Then 4-fluoro-4- [ methoxy (methyl) carbamoyl]Tert-butyl piperidine-1-carboxylate (1.00 g, 3.44 mmol) was added to the reaction. The reaction was stirred at 0 ℃ for 1.5 hours. Reacting with saturated NH₄Aqueous Cl (5 mL) was quenched and diluted with EA (50 mL) and water (30 mL). The aqueous layer was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography, eluting with PE/EA (3/1), and obtaining 4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] in the form of pale yellow oil]Carbonyl radical]4-Fluoropiperidine-1-carboxylic acid tert-butyl ester (0.50 g, 27%): C₂₀H₂₄Cl₂FNO₄ [M + H - 56]LCMS (ESI) calculated for +: 376, 378 (3: 2), measured 376, 378 (3: 2);¹H NMR (400 MHz, CDCl3) δ 7.32 (s, 1H), 7.06 (s, 1H), 6.07-5.94 (m, 1H), 5.46-5.32 (m, 2H), 4.59 (dt, J = 5.6, 1.4 Hz, 2H), 4.10 (d, J = 13.8 Hz, 2H), 3.12-3.01 (m, 2H), 2.15-1.97 (m, 4H), 1.50 (s, 9H)。

step b:

to a stirred 4- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl group at room temperature under nitrogen atmosphere](iii) -4-Fluoropiperidine-1-carboxylic acid tert-butyl ester (0.50 g, 1.16 mmol) and tert-Butanesulfinamide (0.21 g, 1.73 mmol) in THF (8 mL) Ti (OEt)₄(0.79 g, 3.47 mmol). The reaction was stirred at 70 ℃ for 16 hours. The reaction was saturated with Na ₂CO₃Aqueous solution (30 mL) was quenched. The resulting mixture was filtered through celite (celite), the filtrate was diluted with EA (30 mL) and water (30 mL), and the aqueous layer was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE/EA (5/1) to give 4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] in the form of a yellow oil][ (2-methylpropane-2-sulfinyl) imino]Methyl radical]-4-Fluoropiperidine-1-carboxylic acid tert-butyl ester (50 mg, 7%): C₂₄H₃₃Cl₂FN₂O₄S [M + Na]⁺Calculated lcms (esi): 557, 559 (3: 2), found 557, 559 (3: 2);

step c:

to a stirred 4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl group at room temperature][ (2-methylpropane-2-sulfinyl) imino]Methyl radical](iv) -4-Fluoropiperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.09 mmol) in THF (1 mL) NaBH was added₄(7 mg, 0.19 mmol). Reacting with saturated NH₄Aqueous Cl (1 mL) was quenched and diluted with EA (30 mL) and water (30 mL). The aqueous layer was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] as a pale yellow solid ][ (2-methylpropane-2-sulfinyl) amino group]Methyl radical]-4-fluoropiperidine-1-carboxylic acid tert-butyl ester (50 mg, crude), which is used in the next step without further purification: c₂₂H₃₂Cl₂N₂O₄S [M + Na]⁺Lcms (esi) calculated value of (a): 559, 561 (3: 2), found 559, 561 (3: 2).

Step d:

to a stirred 4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl group at room temperature][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]-4-Fluoropiperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.09 mmol) and Pd (PPh)₃)₄(5 mg, 0.05 mmol) in THF (1 mL) NaBH was added₄(7 mg, 0.19 mmol). The reaction was stirred at room temperature for 1 hour. Reacting with saturated NH₄Aqueous Cl (20 mL) was quenched. The resulting mixture was extracted with EA (3X 20 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE/EA (1/1) to give 4- [ (4, 5-dichloro-2-hydroxyphenyl) [ (2-methylpropane-2-sulfinyl) amino ] as a brown yellow oil]Methyl radical]-4-Fluoropiperidine-1-carboxylic acid tert-butyl ester (40 mg, 86% of two steps in total): C₂₁H₃₁Cl₂FN₂O₄S [M + Na]⁺Calculated value of LCMS (ESI): 519, 521 (3: 2), found 519, 521 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.51 (s, 1H), 6.97 (s, 1H), 4.85-4.76 (m, 1H), 4.08-3.79 (m, 2H), 3.19-2.95 (m, 2H), 2.35-2.16 (m, 2H), 1.81-1.53 (m, 2H), 1.46 (s, 9H), 1.15 (s, 9H)。

step e:

to a stirred mixture of 4- [ (4, 5-dichloro-2-hydroxyphenyl) [ (2-methylpropane-2-sulfinyl) amino group at room temperature ]Methyl radical]To a solution of tert-butyl (4-fluoropiperidine-1-carboxylate (40 mg, 0.10 mmol) in 1, 4-dioxane (1 mL) was added aqueous HCl (4N, 1 mL). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The mixture was then dissolved in DCM (2 mL) and TFA (0.5 mL) was added at room temperature. The resulting solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 15% B to 70% B in 7 minutes; a detector: UV 254/210 nm; retention time: 5.90 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure, and yielded compound 59 (2- [ amino (4-fluoropiperidin-4-yl) methyl) as an off-white solid]-4, 5-dichlorophenol trifluoroacetic acid) (8.4 mg, 34%): C₁₂H₁₅Cl₂FN₂O [M + H]⁺Calculated lcms (esi): 293, 295 (3: 2), found 293, 295 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.39 (s, 1H), 6.91 (s, 1H), 4.34 (d, J = 17.4 Hz, 1H), 3.05-2.74 (m, 4H), 2.17-2.02 (m, 1H), 1.83-1.47 (m, 3H)； ¹⁹F NMR (282 MHz, CD₃OD) δ -76.94, -172.46.

example 129 Compound 60 (, (S) -2- [ amino (piperidin-4-yl) methyl]-3,4, 5-trichlorophenol trifluoroacetic acid)) and compound 61 (, (i.e., (ii) (trichlorophenol trifluoroacetic acid))R) -2- [ amino (piperidin-4-yl) methyl ]-3,4, 5-trichlorophenol trifluoroacetic acid)

A, step a:

to stirred (3,4, 5-trichlorophenyl) boronic acid (6.00 g, 26.64 mol) and H under nitrogen atmosphere at room temperature₂O₂(1.81 g, 53.27 mmol, 30%) to a solution in THF (10 mL) was added NaOH (2.13 g, 53.27 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 12 hours. The reaction was saturated with Na₂SO₃Quench with aqueous solution (100 mL) and use aqueous HCl (1)N) Acidifying to pH 3-4. The resulting mixture was extracted with EA (3X 100 mL). The combined organic layers were washed with brine (3X 100 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (9/1) to give 3,4, 5-trichlorophenol (3.10 g, 88%) as a pale yellow solid. C₆H₂Cl₃O[M - H]^-Calculated lcms (esi): 195, 197, 199 (3: 3: 1), found 195, 197, 199 (3: 3: 1);¹H NMR (300 MHz, DMSO-d ₆) δ 10.55 (s, 1H), 6.99 (s, 1H)。

step b:

AlCl was added dropwise to a stirred mixture of 3,4, 5-trichlorophenol (0.59 g, 2.99 mmol), acetamide (0.21 g, 3.59 mmol) and pyridine-4-carbaldehyde (0.32 g, 2.99 mmol) at 110 ℃ under nitrogen₃(59.8 mg, 0.45 mmol). The reaction mixture was stirred at 110 ℃ for 10 hours. After cooling to room temperature, the reaction mixture was quenched with water (200 mL) at room temperature. The resulting mixture was extracted with EA (3X 80 mL). The combined organic layers were washed with brine (3X 10 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 50% aqueous ACN (plus 0.05% TFA) to afford the title compound as a pale yellow oilN- [ pyridin-4-yl (2,3, 4-trichloro-6-hydroxyphenyl) methyl group]Acetamide (0.14 g, 12%). C₁₄H₁₁Cl₃N₂O₂ [M + H]⁺Calculated lcms (esi): 345, 347 (1: 1), found 345, 347 (1: 1);¹H NMR (300 MHz, CD₃OD) δ 8.81-8.67 (m, 2H), 7.97-7.86 (m, 2H), 7.13 (s, 1H), 7.05 (s, 1H), 2.17 (s, 3H)。

step c:

to the direction ofN- [ pyridin-4-yl (2,3, 4-trichloro-6-hydroxyphenyl) methyl group]A solution of acetamide (0.10 g, 0.29 mmol) in the cosolvent MeOH/AcOH (20 mL, v/v =1:1) was added to PtO in a pressure tank₂(20 mg). The mixture was hydrogenated under hydrogen atmosphere (50 atm) at 30 ℃ for 6 hours. The resulting mixture was filtered through celite (celite), and the filtrate was concentrated under reduced pressure to obtain a colorless oilN- [ piperidin-4-yl (2,3, 4-trichloro-6-hydroxyphenyl) methyl group]Acetamide (0.10 g, crude). C₁₄H₁₇Cl₃N₂O₂ [M + H]+Calculated lcms (esi): 351, 353, 355 (3: 3: 1), found 351, 353, 355 (3: 3: 1);¹H NMR (300 MHz, CD₃OD) δ 6.97 (s, 1H), 5.51 (d, J =10.5 hours z, 1H), 3.45 (d,J = 12.7 Hz, 1H), 3.40-3.34 (m, 1H), 3.07-2.82 (m, 2H), 2.30-2.13 (m, 1H), 1.98 (s, 3H), 1.58-1.46 (m, 1H), 1.35-1.25 (m, 3H)。

step d:

stirred in the downward direction at 100 deg.CN- [ pyridin-4-yl (2,3, 4-trichloro-6-hydroxyphenyl) methyl group]A solution of acetamide (0.14 g, 0.4 mmol) in concentrated HCl (3 mL) for 3 hours. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 5% B to 40% B in 8 minutes; a detector: UV 254/210 nm; retention time: 7.18 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure to give 2- [ amino (piperidin-4-yl) methyl ] as a pale yellow solid ]-3,4, 5-trichlorophenol trifluoroacetic acid (70 mg, 41%). C₁₂H₁₅Cl₃N₂O [M + H]⁺Calculated lcms (esi): 309, 311, 313 (3: 3: 1), found 309, 311, 313 (3: 3: 1).¹H NMR (400 MHz, CD₃OD) δ 7.15 (s, 1H), 4.69 (d, J = 10.1 Hz, 1H), 3.55 (d, J = 12.9 Hz, 1H), 3.38 (d, J = 12.9 Hz, 1H), 3.05 (td, J = 13.1, 3.1 Hz, 1H), 2.94 (td, J = 12.4, 5.3 Hz, 1H), 2.73-2.66 (m, 1H), 2.26 (d, J = 13.9 Hz, 1H), 1.80-1.49 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.06.

Step e:

isolation of 2- [ amino (piperidin-4-yl) methyl group by preparation of SFC]-3,4, 5-trichlorophenol trifluoroacetic acid (68 mg, 0.16 mmol) column: CHIRALPAK IG UL001, 20 × 250 mm, 5 μm; mobile phase A: CO 2₂And the mobile phase B: MeOH (0.5% IPA); flow rate: 40 mL/min; gradient: 35% of B; a detector: UV 220 nm; retention time: RT (reverse transcription)₁2.56 minutes; RT (reverse transcription)₂5.4 minutes; the temperature is 25 ℃.

The faster eluting enantiomer was obtained as compound 61 (, (r) in the form of a pale yellow solid at 2.56 minR) -2- [ amino (piperidin-4-yl) methyl]-3,4, 5-trichlorophenol trifluoroacetic acid) (5.1 mg, 8%): C₁₂H₁₅C_l3N₂O [M + H]⁺Calculated lcms (esi): 309, 311, 313 (3: 3: 1), found 309, 311, 313 (3: 3: 1);¹H NMR (400 MHz, DMSO-d ₆) δ 7.17 (s, 1H), 4.40 (d, J = 10.0 Hz, 1H), 3.38 (d, J = 12.9 Hz, 1H), 3.21 (d, J = 12.8 Hz, 1H), 2.95-2.70 (m, 2H), 2.48-2.39 (m, 1H), 2.10 (d, J = 13.9 Hz, 1H), 1.57-1.45 (m, 1H), 1.39-1.25 (m, 2H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -73.50.

the slower eluting enantiomer was obtained as compound 60 (, (r) in the form of a pale yellow solid at 5.4 minS) -2- [ amino (piperidin-4-yl) methyl]-3,4, 5-trichlorophenol trifluoroacetic acid) (6.5 mg, 9%): C₁₂H₁₅Cl₃N₂O [M + H]⁺Calculated lcms (esi): 309, 311, 313 (3: 3: 1), found 309, 311, 313 (3: 3: 1); ¹H NMR (400 MHz, DMSO-d ₆) δ 7.19 (s, 1H), 4.40 (d, J = 10.1 Hz, 1H), 3.39 (d, J = 12.7 Hz, 1H), 3.21 (d, J = 12.9 Hz, 1H), 2.93-2.73 (m, 2H), 2.48-2.39 (m, 1H), 2.16-2.02 (m, 1H), 1.57-1.42 (m, 1H), 1.42-1.28 (m, 2H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -73.51.

EXAMPLE 130 Compound 62 (amino (1- (2, 2-difluoroethyl) piperidin-4-yl) methyl) -4, 5-dichlorophenol trifluoroacetic acid)

Step a:

under nitrogen atmosphere at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]To a solution of-2-methylpropane-2-sulfinamide (0.20 g, 0.48 mmol) and 1, 1-difluoro-2-iodoethane (0.27 g, 1.43 mmol) in MeCN (3 mL) was added K₂CO₃(0.13 g, 0.95 mmol). The reaction mixture was warmed to 50 ℃ and stirred under nitrogen for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (30 mL) and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with a solution containing 10 mmol/L NH₄HCO₃Was eluted with 70% aqueous ACN solution to give a pale yellow solidN- ((2- (allyloxy) -4, 5-dichlorophenyl) (1- (2, 2-difluoroethyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (0.12 g, 52%): C₂₁H₃₀Cl₂F₂N₂O₂S [M + H]⁺Calculated lcms (esi): 483, 485 (3: 2), found 483, 485 (3: 2).

Step b:

under nitrogen atmosphere at room temperature with stirringN- ((2- (allyloxy) -4, 5-dichlorophenyl) (1- (2, 2-difluoroethyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (0.12 g, 0.25 mmol) and Pd (PPh) ₃)₄(6 mg, 0.01 mmol) in THF (10 mL) was added NaBH portionwise₄(14 mg, 0.38 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction mixture was quenched with water (30 mL) at room temperature. The resulting mixture was extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by preparative TLC, eluting with PE/EA (4/1) to give as a yellow solidN- ((4, 5-dichloro-2-hydroxyphenyl) (1- (2, 2-difluoroethyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (80 mg, 73%): C₁₈H₂₆Cl₂F₂N₂O₂S [M + H]⁺Lcms (esi) calculated value of (a): 443, 445 (3: 2), found 443, 445 (3: 2);

step c:

at room temperature with stirringNTo a solution of (- ((4, 5-dichloro-2-hydroxyphenyl) (1- (2, 2-difluoroethyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (50 mg, 0.11 mmol) in DCM (2 mL) was added TFA (1 mL). The reaction solution was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column, 5 μm, 19X 150 mm; mobile phase A: water (plus 0.5% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 10% B to 35% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.5 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 62 (2- (amino (1- (2, 2-difluoroethyl) piperidin-4-yl) methyl) -4, 5-dichlorophenol trifluoroacetic acid) (10 mg, 23%) as a pale yellow solid as C ₁₄H₁₈Cl₂F₂N₂O [M + H]⁺Lcms (esi) calculated value of (a): 339, 341 (3: 2), found 339, 341 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.46 (s, 1H), 7.10 (s, 1H), 6.30 (t, J =54.0 Hz； 1 H), 4.25 (d, J = 9.6 Hz； 1 H), 3.70-3.33 (m, 4H), 3.12-2.80 (m, 2H), 2.51-2.30 (m, 1H), 2.22-2.10 (m, 1H), 1.80-1.62 (m, 1H), 1.59-1.46 (m, 2H)； ¹⁹F NMR (282 MHz, CD₃OD) δ -77.04, -121.72。

example 131 Compound 63 ((4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) ((S) -pyrrolidin-3-yl) methanone trifluoroacetic acid

Step a:

under nitrogen atmosphere at room temperature with stirringN- ((2- (allyloxy) -4, 5-dichlorophenyl) (piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (0.20 g, 0.48 mmol) andS) (iv) -1- (tert-Butoxycarbonyl) pyrrolidine-3-carboxylic acid (0.15 g, 0.72 mmol) in DMF (3 mL) was added Et₃N (0.15 g, 1.44 mmol) and EDCI (0.18 g, 0.96 mmol). The reaction solution was stirred at room temperature under nitrogen atmosphere for 1 hour. The resulting solution was quenched with water (40 mL) at room temperature and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE/EA (1/1) to give (3) as a pale yellow solidS) Tert-butyl (3- (4- ((2- (allyloxy) -4, 5-dichlorophenyl) (1, 1-dimethylethylenesulfonamido) methyl) piperidine-1-carbonyl) pyrrolidine-1-carboxylate (0.18 g, 60%): C₂₉H₄₃Cl₂N₃O₅S [M + H]⁺Calculated lcms (esi): 616, 618 (3: 2), found 616, 618 (3: 2).

Step b:

stirred at room temperature under nitrogen atmosphere (3)S) Tert-butyl (0.18 g, 0.29 mmol) 3- (4- ((2- (allyloxy) -4, 5-dichlorophenyl) (1, 1-dimethylethylenesulfonamido) methyl) piperidine-1-carbonyl) pyrrolidine-1-carboxylate and Pd (PPh)₃)₄(32 mg, 0.029 mmol) in THF (5 mL) NaBH was added₄(16 mg, 0.44 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. The resulting mixture was quenched with water (40 mL) at room temperature and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give crude (3)S) -tert-butyl 3- (4- ((4, 5-dichloro-2-hydroxyphenyl) (1, 1-dimethylethylenesulfonamido) methyl) piperidine-1-carbonyl) pyrrolidine-1-carboxylate. The crude product was used without further purification in the subsequent step: c₂₆H₃₉Cl₂N₃O₅S [M + H]⁺Calculated lcms (esi): 576, 578 (3: 2), found 576, 578 (3: 2).

Step c:

stirring at room temperature (3)S) To a solution of tert-butyl (crude) 3- (4- ((4, 5-dichloro-2-hydroxyphenyl) (1, 1-dimethylethylenesulfonamido) methyl) piperidine-1-carbonyl) pyrrolidine-1-carboxylate in 1, 4-dioxane (5 mL) was added aqueous HCl (6 mL) N3 mL). The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was dissolved in DCM (5 mL), and TFA (3 mL) was added at room temperature. The reaction solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: column: xbridge C18 OBD Prep Column, 100A, 10 μm, 19 mm × 250 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 5% B to 45% B in 7 minutes; a detector: UV 254/210 nm; retention time: 5.52. the fractions containing the desired product were collected and concentrated under reduced pressure to give compound 63 ((4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) ((s) (b) as an off-white solidS) -pyrrolidin-3-yl) methanone trifluoroacetic acid) (56.2 mg, 40% two-step total) C₁₇H₂₃Cl₂N₃O₂ [M + H]⁺Calculated lcms (esi): 372, 374 (3: 2), measured 372, 374 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.44 (d, J = 3.6 Hz, 1H), 7.09 (d, J =2.2 Hz, 1H), 4.58 (dd, J = 41.8, 13.3 Hz, 1H), 4.26-3.96 (m, 2H), 3.74-3.54 (m, 2H), 3.41-3.30 (m, 3H), 3.26-3.00 (m, 1H), 2.80-2.54 (m,1H), 2.49-2.31 (m, 2H), 2.21-2.02 (m, 2H), 1.59-1.08 (m, 3H)； ¹⁹F NMR (282 MHz, CD₃OD) δ -76.92。

EXAMPLE 132 Compound 64 (2- (amino (1- (2-methoxyethyl) piperidin-4-yl) methyl) -4, 5-dichlorophenol)

Step a:

at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]To a solution of-2-methylpropane-2-sulfinamide (0.18 g, 0.43 mmol) and DIEA (0.11 g, 0.86 mmol) in ACN (3 mL) was added 1-bromo-2-methoxyethane (0.18 g, 1.29 mmol) in portions. The reaction solution was stirred at room temperature for 1 hour. The resulting solution was diluted with water (30 mL) and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with a solution containing 10 mmol/L NH₄HCO₃Eluting with 50% aqueous ACN solution to obtain a yellow solidN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (2-methoxyethyl) piperidin-4-yl group]Methyl radical]2-methylpropane-2-sulfinamide (0.17 g, 75%): C₂₂H₃₄Cl₂N₂O₃S [M + H]⁺Calculated lcms (esi): 477, 479 (3: 2), found 477, 479 (3: 2).

Step b:

under nitrogen atmosphere at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (2-methoxyethyl) piperidin-4-yl group]Methyl radical]-2-methylpropane-2-sulfinamide (0.17 g, 0.36 mmol) and Pd (PPh)₃)₄(45 mg, 0.04 mmol) in THF (2 mL) NaBH was added portionwise₄(27 mg, 0.71 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. The reaction mixture was quenched with water (30 mL) at room temperature and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give a crude productN- ((4, 5-dichloro-2-hydroxyphenyl) (1- (2-methoxyethyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide. The crude product was used without further purification in the subsequent step: c ₁₉H₃₀Cl₂N₂O₃S [M + H]⁺Calculated lcms (esi): 437, 439 (3: 2), found 437, 439 (3: 2);

step c:

at room temperature with stirringNTo a solution of (- ((4, 5-dichloro-2-hydroxyphenyl) (1- (2-methoxyethyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (crude) in 1, 4-dioxane (2 mL) was added aqueous HCl (6 mL)N1 mL). The reaction solution was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C₁₈OBD Prep Column, 100A 10 μm, 19 mm × 250 mm; mobile phase A: having a NH concentration of 20 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 34% B to 50% B in 6.5 minutes; a detector: UV 254/210 nm; retention time: 5.80 minutes. The fractions containing the desired product were collected and concentrated to give compound 64 (2- (amino (1- (2-methoxyethyl) piperidin-4-yl) methyl) -4, 5-dichlorophenol) (25 mg, 31% two-step total): C as an off-white solid₁₅H₂₂Cl₂N₂O₂ [M + H]⁺Calculated lcms (esi): 333, 335 (3: 2), found 333, 335 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.16 (s, 1H), 6.83 (s, 1H), 3.86 (d, J = 7.9 Hz, 1H), 3.51 (t, J = 5.7 Hz, 2H), 3.30 (s, 3H), 3.06 (d, J = 11.9 Hz, 1H), 2.95 (d, J = 11.6 Hz, 1H), 2.55 (t, J = 5.7 Hz, 2H), 2.16-1.87 (m, 3H), 1.82-1.69 (m, 1H), 1.46-1.21 (m, 3H)。

EXAMPLE 133 Compound 65 (3- (4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) pyrrolidin-2-one trifluoroacetic acid)

Step a:

At room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]To a solution of-2-methylpropane-2-sulfinamide (0.18 g, 0.43 mmol) and DIEA (0.11 g, 0.86 mmol) in ACN (3 mL) was added 3-bromopyrrolidin-2-one (0.21 g, 1.29 mmol) in portions. The reaction solution was stirred at room temperature for 10 hours. The resulting solution was diluted with water (30 mL) and extracted with EA (2X 30 mL). Combining the organic layers withWashed with brine (2X 20 mL) over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with a solution containing 10 mmol/L NH₄HCO₃Eluting with 40% -70% ACN water solution to obtain yellow solidN- ((2- (allyloxy) -4, 5-dichlorophenyl) (1- (2-oxopyrrolidin-3-yl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (0.15 g, 63%): C₂₃H₃₃Cl₂N₃O₃S [M + H]⁺Calculated lcms (esi): 502, 504 (3: 2), found 502, 504 (3: 2).

Step b:

under nitrogen atmosphere at room temperature with stirringN- ((2- (allyloxy) -4, 5-dichlorophenyl) (1- (2-oxopyrrolidin-3-yl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (0.15 g, 0.30 mmol) and Pd (PPh)₃)₄(34 mg, 0.03 mmol) to a mixture in THF (5 mL) NaBH was added portionwise ₄(17 mg, 0.45 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction mixture was quenched with water (30 mL) at room temperature. The resulting mixture was extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give a crude productN- ((4, 5-dichloro-2-hydroxyphenyl) (1- (2-oxopyrrolidin-3-yl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide. The crude product was used without further purification in the subsequent step: c₂₀H₂₉Cl₂N₃O₃S [M + H]⁺Calculated lcms (esi): 462, 464 (3: 2), found 462, 464 (3: 2)

Step c:

at room temperature with stirringNTo a solution of (- ((4, 5-dichloro-2-hydroxyphenyl) (1- (2-oxopyrrolidin-3-yl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (crude) in 1, 4-dioxane (4 mL) was added aqueous HCl (6 mL)N2 mL). The reaction solution was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column, 100A, 10 μm, 19mm is multiplied by 250 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 5% B to 30% B in 8 minutes; a detector: UV 254/210 nm; retention time: 6.37 minutes. The fractions containing the desired product were collected and concentrated to give compound 65 (3- (4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) pyrrolidin-2-one trifluoroacetic acid) (60 mg, 56% two steps total) C as an off-white solid ₁₆H₂₁Cl₂N₃O₂ [M + H]⁺Lcms (esi) calculated value of (a): 358, 360 (3: 2), found 358, 360 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.48 (s, 1H), 7.11 (s, 1H), 4.33-4.18 (m, 2H), 4.15-3.74 (m, 1H), 3.67-3.38 (m, 4H), 3.23-3.00 (m, 1H), 2.58-2.24 (m, 4H), 1.88-1.50 (m, 3H)。

example 134 Compound 66 ((4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) ((R)R) -pyrrolidin-3-yl) methanone trifluoroacetic acid)

A, step a:

under nitrogen atmosphere, stirred at room temperatureN- ((2- (prop-2-en-1-yloxy) -4, 5-dichlorophenyl) (piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (intermediate 5, example 5) (0.20 g, 0.48 mmol) and (C) (I)R) (iv) -1- (tert-Butoxycarbonyl) pyrrolidine-3-carboxylic acid (0.15 g, 0.72 mmol) in DMF (3 mL) was added Et₃N (0.15 g, 1.44 mmol) and EDCI (0.18 g, 0.96 mmol). The reaction solution was stirred at room temperature for 1 hour under a nitrogen atmosphere. The resulting solution was quenched with water (40 mL) at room temperature and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE/EA (1/1) to give (3) as a pale yellow solidR) Tert-butyl (3- (4- ((2- (prop-2-en-1-yloxy) -4, 5-dichlorophenyl) (1, 1-dimethylethylenesulfonamido) methyl) piperidine-1-carbonyl) pyrrolidine-1-carboxylate (0.19 g, 62%): C ₂₉H₄₃Cl₂N₃O₅S [M + H]⁺Lcms (esi) calculated value of (a): 616, 618 (3: 2), found 616, 618 (3: 2).

Step b:

stirring under nitrogen atmosphere at room temperatureR) -tert-butyl 3- (4- ((2- (prop-2-en-1-yloxy) -4, 5-dichlorophenyl) (1, 1-dimethylethylenesulfonamido) methyl) piperidine-1-carbonyl) pyrrolidine-1-carboxylate (0.19 g, 0.31 mmol) and Pd (PPh)₃)₄(35 mg, 0.031 mmol) in THF (5 mL) NaBH was added₄(18 mg, 0.47 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. The resulting mixture was quenched with water (40 mL) at room temperature and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give crude (3)R) -tert-butyl 3- (4- ((4, 5-dichloro-2-hydroxyphenyl) (1, 1-dimethylethylenesulfonamido) methyl) piperidine-1-carbonyl) pyrrolidine-1-carboxylate. The crude product was used without further purification in the subsequent step: c₂₆H₃₉Cl₂N₃O₅S [M + H]⁺Calculated lcms (esi): 576, 578 (3: 2), found 576, 578 (3: 2).

Step c:

stirring at room temperature (3)R) To a solution of tert-butyl (crude) 3- (4- ((4, 5-dichloro-2-hydroxyphenyl) (1, 1-dimethylethylenesulfonamido) methyl) piperidine-1-carbonyl) pyrrolidine-1-carboxylate in 1, 4-dioxane (5 mL) was added aqueous HCl (6 mL) N3 mL). The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was dissolved in DCM (5 mL), then TFA (3 mL) was added at room temperature. The reaction solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: column: xbridge C18 OBD Prep Column, 100A, 10 μm, 19 mm × 250 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 5% B to 45% B in 7 minutes; a detector: UV 254/210 nm; retention time: 5.52. collecting the fraction containing the desired productDivided and concentrated under reduced pressure to give compound 66 ((4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) ((s) as an off-white solidR) -pyrrolidin-3-yl) methanone trifluoroacetic acid) (60.1 mg, 42% two-step total): C₁₇H₂₃Cl₂N₃O₂ [M + H]⁺Calculated lcms (esi): 372, 374 (3: 2), measured 372, 374 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.44 (d, J = 3.6 Hz, 1H), 7.09 (d, J =2.2 Hz, 1H), 4.58 (dd, J = 41.8, 13.3 Hz, 1H), 4.26-3.96 (m, 2H), 3.74-3.54 (m, 2H), 3.41-3.30 (m, 3H), 3.26-3.00 (m, 1H), 2.80-2.54 (m,1H), 2.49-2.31 (m, 2H), 2.21-2.02 (m, 2H), 1.59-1.08 (m, 3H)； ¹⁹F NMR (282 MHz, CD₃OD) δ -76.92。

EXAMPLE 135 Compound 67 (2- [ amino [1- (oxetane-3-carbonyl) piperidin-4-yl ] methyl ] -4, 5-dichlorophenol)

Step a:

to a stirred solution of HATU (0.42 g, 1.09 mmol) and oxetane-3-carboxylic acid (75 mg, 0.73 mmol) in DMF (3 mL) under a nitrogen atmosphere at room temperature was added Et ₃N (0.12 g, 1.09 mmol) andN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]-a solution of 2,2, 2-trifluoroacetamide (0.15 g, 0.36 mmol) in DMF (2 mL). After stirring at room temperature for an additional 2 hours, the reaction solution was quenched with water (20 mL) at room temperature and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EA (5/1) to give a yellow solidN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (Oxetane-3-carbonyl) piperidin-4-yl group]Methyl radical]-2,2, 2-trifluoroacetamide (0.13 g, 72%): C₂₁H₂₃Cl₂F₃N₂O₄ [M + H]⁺Calculated lcms (esi): 495497 (3: 2), found 495, 497 (3: 2).

Step b:

at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (Oxetane-3-carbonyl) piperidin-4-yl group]Methyl radical]To a solution of-2, 2, 2-trifluoroacetamide (0.20 g, 0.40 mmol) in MeOH/water (10 mL/5 mL) was added KOH (0.11 g, 2.00 mmol). The reaction mixture was stirred at room temperature for 6 hours and diluted with water (30 mL) at room temperature. The resulting mixture was extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 1- [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]-1- [1- (oxetane-3-carbonyl) piperidin-4-yl]Methylamine (0.10 g, crude). The crude product was used in the next step without further purification as a yellow solid: c₁₉H₂₄Cl₂N₂O₃ [M + H]⁺Calculated lcms (esi): 399, 401 (3: 2), found 399, 401 (3: 2).

Step c:

to a stirred 1- [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl group at room temperature under a nitrogen atmosphere]-1- [1- (oxetane-3-carbonyl) piperidin-4-yl]Methylamine (0.10 g, 0.25 mmol) and Pd (PPh)₃)₄(6 mg, 0.01 mmol) in THF was added portionwise to the NaBH₄(14 mg, 0.38 mmol). After stirring at room temperature for 1 hour under a nitrogen atmosphere, the reaction mixture was quenched with water (20 mL) at room temperature. The resulting mixture was extracted with EA (2X 20 mL). The aqueous layer was collected and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column, 5 μm, 19X 150 mm; a mobile phase A: having a NH concentration of 10 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 10% B to 35% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.5 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 67 (2- [ amino [1- (oxetane-3-carbonyl) piperidin-4-yl) piperidine as an off-white solid ]Methyl radical]-4, 5-dichlorophenol) (18 mg, 20%): C₁₆H₂₀Cl₂N₂O₃ [M + H]LCMS (ESI) calculated for +: 359, 361 (3: 2), found 359, 361 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.43 (s, 1H), 7.08 (s, 1H), 4.90-4.75 (m, 4 H), 4.60 (dd, J = 36.8, 1.3 Hz； 1 H), 4.20-4.08 (m, 2H), 3.50 (dd, J = 36.8, 1.3 Hz； 1H), 3.12-2.88 (m, 1H), 2.78-2.58 (m, 1H), 2.45-2.26 (m, 1H), 2.10-1.90 (m, 1H), 1.49-1.01 (m, 3H)。

EXAMPLE 136 Compound 68 (2- [ amino (1-benzoylpiperidin-4-yl) methyl ] -4, 5-dichlorophenol trifluoroacetic acid)

Step a:

to a stirred solution of HATU (0.42 g, 1.09 mmol) and benzoic acid (89 mg, 0.72 mmol) in DMF (5 mL) was added dropwise at room temperature under a nitrogen atmosphereN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]-solution of 2,2, 2-trifluoroacetamide (0.15 g, 0.36 mmol) in DMF (2 mL) and Et₃N (0.11 g, 1.09 mmol). The reaction solution was stirred at room temperature under nitrogen atmosphere for 2 hours. The resulting solution was quenched with water (30 mL) at room temperature and extracted with EA (3X 20 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with PE/EA (5/1), to obtain as a yellow solidN- ((2- (allyloxy) -4, 5-dichlorophenyl) (1-benzoylpiperidin-4-yl) methyl) -2,2, 2-trifluoroacetamide (0.12 g, 78%): C₂₄H₂₃Cl₂F₃N₂O₃ [M + H]⁺Calculated lcms (esi): 515, 517 (3: 2), found 515, 517 (3: 2).

Step b:

at room temperature with stirringNTo a solution of (- (2- (allyloxy) -4, 5-dichlorophenyl) (1-benzoylpiperidin-4-yl) methyl) -2,2, 2-trifluoroacetamide (0.12 g, 0.23 mmol) in MeOH/water (10 mL/5 mL) was added KOH (64 mg, 1.15 mmol). Reacting at room temperatureThe mixture was stirred for 6 hours. The resulting mixture was diluted with water (30 mL) and extracted with EA (3X 50 mL) at room temperature. The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. The crude product, as a yellow solid, was used without further purification in the next step: c₂₂H₂₄Cl₂N₂O₂ [M + H]⁺Calculated lcms (esi): 419, 421 (3: 2), found 419, 421 (3: 2).

Step c:

to stirred (4- ((2- (allyloxy) -4, 5-dichlorophenyl) (amino) methyl) piperidin-1-yl) (phenyl) methanone (0.15 g, crude) and Pd (PPh) at room temperature under a nitrogen atmosphere₃)₄ (7 mg, 0.01 mmol) in THF was added NaBH4 (18 mg, 0.47 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. The resulting mixture was quenched with water (20 mL) at room temperature and extracted with EA (3X 30 mL). The aqueous layer was collected and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column, 5 μm, 19X 150 mm; mobile phase A: water (plus 0.5% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 10% B to 35% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.5 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 68 (2- [ amino (1-benzoylpiperidin-4-yl) methyl) as an off-white solid ]-4, 5-dichlorophenol trifluoroacetic acid) (63 mg, 52%): C₁₉H₂₀Cl₂N₂O₂ [M + H]⁺Lcms (esi) calculated value of (a): 379, 381 (3: 2), found 379, 381 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.48-7.42 (m, 6H), 7.08 (s, 1H), 4.80-4.65 (m, 1 H), 4.20 (d, J = 9.6 Hz； 1 H), 3.98-3.65 (m, 1 H), 3.20-2.65 (m, 2H), 2.50-2.31 (m, 1H), 2.12-1.88 (m, 1H), 1.59-1.11 (m, 3H)； ¹⁹F NMR (282 MHz, CD₃OD) δ -77.00。

example 137 Compound 69 (, (R) -2-amino-1- (4- ((s))R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) propan-1-one) and compounds87 ((R) -2-amino-1- (4- ((s))S) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) propan-1-one)

Step a:

separation by chiral preparative HPLC under the following conditions (2)R) -2-amino-1- (4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) propan-1-one (50 mg) column: column: CHIRALPAK IG UL001, 20X 250 mm, 5 μm; mobile phase A: hexane (plus 0.2% IPA), mobile phase B: EtOH; flow rate: 18 mL/min; gradient: from 40% B to 40% B in 16 minutes; a detector: UV 254/220 nm; retention time: RT (reverse transcription)₁11.55 minutes; RT (reverse transcription)₂15.73 minutes; injection volume 0.3 mL.

The faster eluting enantiomer was obtained as compound 87 (,(s) as an off-white solid at 11.55 minutesR) -2-amino-1- (4- ((s))S) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) propan-1-one) (6.3 mg, 13%): C₁₅H₂₁Cl₂N₃O₂ [M + H]⁺Calculated lcms (esi): 346, 348 (3: 2), found 346, 348 (3: 2); ¹H NMR (400 MHz, CD₃OD) δ 7.22 (d, J = 11.9 Hz, 1H), 6.86 (d, J = 5.1 Hz, 1H), 4.55 (dd, J = 36.6, 13.5 Hz, 1H), 4.08-3.73 (m, 3H), 3.18-2.94 (m, 1H), 2.71-2.55 (m, 1H), 2.14-1.92 (m, 2H), 1.59-1.42 (m, 1H), 1.38-1.11 (m,5H)。

The slower eluting enantiomer was obtained as compound 69 (, (r) as an off-white solid at 15.73 minutesR) -2-amino-1- (4- ((s))R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) propan-1-one) (2.1 mg, 4%): C₁₅H₂₁Cl₂N₃O₂ [M + H]⁺Calculated lcms (esi): 346, 348 (3: 2), found 346, 348 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.22 (d, J = 3.7 Hz, 1H), 6.87 (s, 1H), 4.56 (dd, J = 13.3, 38.9 Hz, 1H), 4.06-3.85 (m, 3H), 3.18-2.97 (m, 1H), 2.70-2.52 (m, 1H), 2.14-1.92 (m, 2H), 1.59-1.42 (m, 1H), 1.38-1.11 (m,5H)。

EXAMPLE 138 Compound 70 (2- [ amino [1- (pyridin-2-yl) piperidin-4-yl ] methyl ] -4, 5-dichlorophenol trifluoroacetic acid)

Step a:

under nitrogen atmosphere at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide (0.30 g, 0.72 mmol) and 2-fluoropyridine (0.14 g, 1.43 mmol) in DMF (8 mL) was addedtBuOK (0.24 g, 2.15 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The resulting mixture was diluted with water (30 mL) and extracted with EA (3X 30 mL). The combined organic layers were washed with water (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography using a column containing 20 mmol/L NH₄HCO₃Eluting with 65% ACN aqueous solution to obtain a light yellow oilN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ][1- (pyridin-2-yl) piperidin-4-yl group]Methyl radical]-2-methylpropane-2-sulfinamide (80 mg, 22%): C₂₄H₃₁Cl₂N₃O₂S [M + H]⁺Calculated lcms (esi): 496, 498 (3: 2), found 496, 498 (3: 2).

Step b:

under nitrogen atmosphere at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (pyridin-2-yl) piperidin-4-yl group]Methyl radical]-2-methylpropane-2-sulfinamide (80 mg, 0.16 mmol) and Pd (PPh)₃)₄(37 mg, 0.03 mmol) in THF (3 mL) NaBH was added₄(12 mg, 0.32 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. The resulting mixture was quenched with water (40 mL) at room temperature and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give a crude productN- ((4, 5-dichloro-2-hydroxyphenyl) (1- (pyridin-2-yl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide. The crude product was used without further purification in the subsequent step: c₂₁H₂₇Cl₂N₃O₂S [M + H]⁺Calculated lcms (esi): 456, 458 (3: 2), found 456, 458 (3: 2).

Step c:

at room temperature with stirringNTo a solution of (- ((4, 5-dichloro-2-hydroxyphenyl) (1- (pyridin-2-yl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (crude) in 1, 4-dioxane (3 mL) was added aqueous HCl (6 mL) N1.5 mL). The reaction solution was stirred at room temperature for 2 hours. The resulting solution was diluted with saturated NaHCO₃The aqueous solution was neutralized to pH 7 and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 16% B to 30% B in 8 minutes; a detector: UV 254/210 nm; retention time: 6.23 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 70 (2- [ amino [1- (pyridin-2-yl) piperidin-4-yl) piperidine as an off-white solid]Methyl radical]-4, 5-dichlorophenol trifluoroacetic acid) (5 mg, 11% of the total of the two steps) C₁₇H₁₉Cl₂N₃O [M + H]⁺Calculated lcms (esi): 352, 354 (3: 2), found 352, 354 (3: 2);¹H NMR (300 MHz, DMSO-d ₆ + D₂O) δ 8.04 (dd, J = 4.9, 2.0 Hz, 1H), 7.50-7.39 (m, 1H), 7.27 (s, 1H), 6.84 (s, 1H), 6.76 (d, J = 8.7 Hz, 1H), 6.53 (dd, J = 7.1, 4.9 Hz, 1H), 4.29 (t, J = 16.4 Hz, 2H), 3.87 (d, J = 6.4 Hz, 1H), 2.75-2.55 (m, 2H), 1.90-1.65 (m, 2H), 1.45-1.06 (m, 3H)。

EXAMPLE 139 Compound 71 (2- [ amino (1-methanesulfonylpiperidin-4-yl) methyl ] -4, 5-dichlorophenol trifluoroacetic acid)

Step a:

under nitrogen atmosphere at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]-2,2, 2-trifluoroacetamide (0.15 g, 0.36 mmol) and Et₃To a solution of N (0.11 g) in DCM (5 mL) was added methanesulfonyl chloride (84 mg, 0.73 mmol) dropwise. After stirring at room temperature for an additional 2 hours under a nitrogen atmosphere, the reaction solution was quenched with water (20 mL) at room temperature. The resulting mixture was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica eluting with PE/EtOAc (5/1) to give as a yellow solidN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](1-Methanesulphonylpiperidin-4-yl) methyl]-2,2, 2-trifluoroacetamide (0.11 g, 61%): C₁₈H₂₁Cl₂F₃N₂O₄S [M + H]⁺Calculated lcms (esi): 489, 491 (3: 2), found 489, 491 (3: 2).

Step b:

under nitrogen atmosphere at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](1-Methanesulphonylpiperidin-4-yl) methyl]To a solution of-2, 2, 2-trifluoroacetamide (80 mg, 0.16 mmol) in MeOH/water (5 mL/2 mL) was added KOH (0.11 g, 1.96 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 3 hours. The resulting mixture was diluted with water (10 mL) and extracted with EA (3X 20 mL) at room temperature. The combined organic layers were washed with brine (3X 3 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography using a column containing 20 mmol/L NH₄HCO₃Eluting with 45% aqueous ACN solution to give 1- [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] as a pale yellow solid]-1- (1-methanesulfonylpiperidin-4-yl) methylamine (44 mg, 68%): C ₁₆H₂₂Cl₂N₂O₃S [M + H]⁺Lcms (esi) calculated value of (a): 393, 395 (3: 2), measured value 393, 395 (3 : 2)。

Step c:

to a stirred 1- [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl group at room temperature under a nitrogen atmosphere]-1- (1-Methanesulphonylpiperidin-4-yl) methylamine (0.10 g, 0.25 mmol) and Pd (PPh)₃)₄(6 mg, 0.01 mmol) in THF was added NaBH₄(14 mg, 0.38 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. The resulting mixture was quenched with water (10 mL) at room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column, 5 μm, 19X 150 mm; mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 10% B to 35% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.5 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 71 (2- [ amino (1-methanesulfonylpiperidin-4-yl) methyl) as an off-white solid]-4, 5-dichlorophenol trifluoroacetic acid) (15 mg, 16%): C₁₃H₁₈Cl₂N₂O₃S [M + H]⁺Calculated lcms (esi): 353, 355 (3: 2), found 353, 355 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.44 (s, 1H), 7.09 (s, 1H), 4.21 (d, J = 9.6 Hz； 1 H), 3.85 (d, J = 11.7 Hz； 1 H), 3.70 (d, J = 11.7 Hz； 1H), 2.83 (s, 3H), 2.80-2.58 (m, 2H), 2.32-2.18 (m, 1H), 2.10-2.02 (m, 1H), 1.59-1.20 (m, 3H)； ¹⁹F NMR (282 MHz, CD₃OD) δ -76.96.

EXAMPLE 140 Compound 72 (amino (2, 2-dimethylpiperidin-4-yl) methyl) -4, 5-dichlorophenol trifluoroacetic acid diastereomer 1) and Compound 73 (2- (amino (2, 2-dimethylpiperidin-4-yl) methyl) -4, 5-dichlorophenol trifluoroacetic acid diastereomer 2)

A, step a:

to 4- [ (4, 5-dichloro-2- [ [2- (trimethylsilyl) ethoxy) at room temperature]Methoxy radical]Phenyl radical) [ (2-methylpropane-2-sulfinyl) amino]Methyl radical]-2, 2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (intermediate 50, example 50) (65 mg, 0.10 mmol) in 1, 4-dioxane (2 mL) to a solution of HCl in water (12) was addedN2 mL). The reaction solution was stirred at room temperature for 0.5 hour. The reaction mixture was then concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 19 mm × 250 mm, 10 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 10% B to 40% B in 8 minutes; a detector: UV 254/210 nm; retention time RT₁6.55 minutes; RT (reverse transcription)₂7.05 minutes.

The faster eluting enantiomer was obtained as compound 73 (2- (amino (2, 2-dimethylpiperidin-4-yl) methyl) -4, 5-dichlorophenol trifluoroacetic acid diastereomer 2) (14 mg, 34%) C as an off-white solid₁₄H₂₀Cl₂N₂O [M + H]⁺Calculated lcms (esi): 303, 304 (3: 2), found 303, 304 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.48 (s, 1H), 7.11 (s, 1H), 4.21 (d, J = 9.4 Hz, 1H), 3.27-3.11 (m, 2H), 2.67-2.53 (m, 1H), 2.10-2.01 (m, 1H), 1.65-1.21 (m, 9H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.01。

the slower eluting enantiomer was obtained as compound 72 (2- (amino (2, 2-dimethylpiperidin-4-yl) methyl) -4, 5-dichlorophenol trifluoroacetic acid diastereomer 1) (8 mg, 20%) C as an off-white solid ₁₄H₂₀Cl₂N₂O [M + H]⁺Lcms (esi) calculated value of (a): 303, 304 (3: 2), found 303, 304 (3: 2);¹H NMR (300 MHz, CDCl₃) δ 7.45 (s, 1H), 7.11 (s, 1H), 4.20 (d, J = 9.3 Hz, 1H), 3.43-3.35 (m, 1H), 3.30-3.19 (m, 1H), 2.73-2.58 (m, 1H), 2.21 (d, J =14.0 Hz, 1H), 1.61-1.27 (m, 9H)。； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.01。

EXAMPLE 141 Compound 74 (2- [ amino [1- (1, 3-oxazol-2-yl) piperidin-4-yl ] methyl ] -4, 5-dichlorophenol)

Step a:

at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide (0.20 g, 0.48 mmol) in NMP (5 mL) was addedtBuOK (0.16 g, 1.43 mmol) and 2-bromo-1, 3-oxazole (0.14 g, 0.95 mmol). The reaction mixture was warmed to 150 ℃ and stirred for 2 hours. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with a solution containing 10 mmol/L NH₄HCO₃Eluting with 60% ACN water solution to obtain light yellow oilN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (1, 3-oxazol-2-yl) piperidin-4-yl group]Methyl radical]-2-methylpropane-2-sulfinamide (80 mg, 34%): C₂₂H₂₉Cl₂N₃O₃S [M + H]⁺Calculated lcms (esi): 486, 488 (3: 2), found 486, 488 (3: 2).

Step b:

under nitrogen atmosphere at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (1, 3-oxazol-2-yl) piperidin-4-yl group]Methyl radical]-2-methylpropane-2-sulfinamide (80 mg, 0.16 mmol) and Pd (PPh) ₃)₄(4 mg, 0.03 mmol) in THF (5 mL) NaBH was added₄(12 mg, 0.32 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The resulting mixture was quenched with water (40 mL) at room temperature and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give a crudeN- [ (4, 5-dichloro-2-hydroxyphenyl) [1- (1, 3-oxazol-2-yl) piperidin-4-yl]Methyl radical]-2-methylpropane-2-sulfinamide. The crude product was used without further purification in the subsequent step: c₁₉H₂₅Cl₂N₃O₃S [M + H]⁺Calculated lcms (esi): 446, 448 (3: 2), found 446, 448 (3: 2).

Step c:

at room temperature with stirringN- [ (4, 5-dichloro-2-hydroxyphenyl) [1- (1, 3-oxazol-2-yl) piperidin-4-yl]Methyl radical](iii) -2-methylpropane-2-sulfinamide (50 mg, 0.11 mmol) in 1, 4-dioxane (4 mL) to which was added aqueous HCl (6)N2 mL). The reaction solution was stirred at room temperature for 2 hours. The resulting solution was taken up in saturated NaHCO₃The aqueous solution was neutralized to pH 7 and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase A: having a NH concentration of 20 mmol/L ₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 48% B to 52% B in 6.5 minutes; a detector: UV 254/210 nm; retention time: 5.63 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 74 (2- [ amino [1- (1, 3-oxazol-2-yl) piperidin-4-yl as an off-white solid]Methyl radical]-4, 5-dichlorophenol) (10 mg, 9% of two steps in total): C₁₅H₁₇Cl₂N₃O₂ [M + H]⁺Calculated lcms (esi): 342, 344 (3: 2), found 342, 344 (3: 2);¹H NMR (300 MHz, DMOSd ₆ + D₂OD) δ 7.49 (d, J = 1.0 Hz, 1H), 7.28 (s, 1H), 6.84 (s, 1H), 6.78 (d, J = 1.1 Hz, 1H), 3.97-3.82 (m, 3H), 2.87-2.68 (m, 2H), 1.87-1.61 (m, 2H), 1.42-1.13 (m, 3H)。

EXAMPLE 142 Compound 75 (, (S) -2-amino-1- (4- ((s))S) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) propan-1-one) and compound 76 (((r) (i.e., (r)S) -2-amino-1- (4- ((s))R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) propan-1-one)

Step a:

separation by chiral preparative HPLC under the following conditions (2)S) -2-amino-1- (4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) propan-1-one (50 mg) column: CHIRALPAK IC, 2X 25 cm, 5Mu m; mobile phase A: hexane (plus 0.2% IPA), mobile phase B: EtOH; flow rate: 20 mL/min; gradient: from 30% B to 30% B in 18 minutes; a detector: UV 220/254 nm; retention time: RT (reverse transcription)₁12.47 minutes; RT (reverse transcription)₂15.87 minutes; injection volume 0.3 mL.

The faster eluting enantiomer was obtained as compound 75 in the form of an off-white solid at 12.47 minutes (, (r) (r))S) -2-amino-1- (4- ((s))S) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) propan-1-one) (8.8 mg, 18%): C₁₅H₂₁Cl₂N₃O₂ [M + H]⁺Calculated lcms (esi): 346, 348 (3: 2), found 346, 348 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.25 (d, J = 7.9 Hz, 1H), 6.90 (d, J = 3.2 Hz, 1H), 4.56 (dd, J = 37.8, 13.4 Hz, 1H), 4.15-3.79 (m, 3H), 3.16-2.94 (m, 1H), 2.74-2.52 (m, 1H), 2.16-1.95 (m, 2H), 1.59-1.43 (m, 1H), 1.42-1.09 (m, 5H)。

the slower eluting enantiomer was obtained as compound 76 (, (r) as an off-white solid at 15.87 minS) -2-amino-1- (4- ((s))R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) propan-1-one) (2.7 mg, 5%): C₁₅H₂₁Cl₂N₃O₂ [M + H]⁺Calculated lcms (esi): 346, 348 (3: 2), found 346, 348 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.25 (d, J = 7.9 Hz, 1H), 6.90 (d, J = 3.2 Hz, 1H), 4.56 (dd, J = 37.8, 13.4 Hz, 1H), 4.15-3.79 (m, 3H), 3.16-2.94 (m, 1H), 2.74-2.52 (m, 1H), 2.16-1.95 (m, 2H), 1.59-1.43 (m, 1H), 1.42-1.09 (m, 5H)。

EXAMPLE 143 Compound 77 (1- [4- [ amino (4, 5-dichloro-2-hydroxyphenyl) methyl ] piperidin-1-yl ] -2,2, 2-trifluoroethyl-1-one trifluoroacetic acid)

Step a:

at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl](iii) -2-methylpropane-2-sulfinamide (0.30 g, 0.72 mmol) in 1, 4-dioxane (5 mL) to which was added aqueous HCl (4)N1 mL). The reaction solution was stirred at room temperature for 2 hours. The resulting mixture was taken up in saturated NaHCO₃The aqueous solution was adjusted to pH 7 and concentrated under reduced pressure. The residue was purified by reverse phase chromatography using a column containing 20 mmol/L NH ₄HCO₃Was eluted with 85% aqueous ACN solution to give tert-butyl 4- ((2- (allyloxy) -4, 5-dichlorophenyl) (amino) methyl) piperidine-1-carboxylate (0.35 g, 89%) as a brown oil C₂₀H₂₈Cl₂N₂O₃ [M + H]⁺Lcms (esi) calculated value of (a): 415, 417 (3: 2), found 415, 417 (3: 2).

Step b:

to a stirred mixture of tert-butyl 4- ((2- (allyloxy) -4, 5-dichlorophenyl) (amino) methyl) piperidine-1-carboxylate (0.35 g, 0.96 mmol) and Et at room temperature under a nitrogen atmosphere₃A solution of N (0.19 g, 1.93 mmol) in DCM (5 mL) was added (9)HFluoren-9-yl) methylcarbonyl chloride (0.37 g, 1.44 mmol). The reaction solution was stirred at room temperature under nitrogen atmosphere for 2 hours. The resulting solution was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (5/1) to give 4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] as an off-white foam]([[(9H-fluoren-9-yl) methoxy]Carbonyl radical]Amino) methyl group]Piperidine-1-carboxylic acid tert-butyl ester (0.35 g, 65%): C₃₅H₃₈Cl₂N₂O₅ [M + H]⁺Calculated lcms (esi): 637, 639 (3: 2), found 637, 639 (3: 2).

Step c:

to a stirred 4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl group at room temperature]([[(9H-fluoren-9-yl) methoxy]Carbonyl radical]Amino) methyl group]To a solution of tert-butyl piperidine-1-carboxylate (0.35 g, 0.55 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with DCM/MeOH (15/1) to afford the title compound as an off-white solid N- [ [4, 5-dichloro-2- (prop-2-en-1-yl)Oxy) phenyl](piperidin-4-yl) methyl]Carbamic acid (9)HFluoren-9-yl) methyl ester (0.16 g, 54%): C₃₀H₃₀Cl₂N₂O₃ [M + H]⁺Calculated lcms (esi): 537, 539 (3: 2), found 537, 539 (3: 2).

Step d:

under nitrogen atmosphere at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]Carbamic acid (9)HFluoren-9-yl) methyl ester (160 mg, 0.30 mmol) and Et₃To a solution of N (60 mg, 0.60 mmol) in DCM (2 mL) was added 2,2, 2-trifluoroacetic anhydride (0.13 g, 0.60 mmol). The reaction solution was stirred at room temperature under nitrogen atmosphere for 1 hour. The resulting solution was concentrated under reduced pressure to give ((2- (allyloxy) -4, 5-dichlorophenyl) (1- (2,2, 2-trifluoroacetyl) piperidin-4-yl) methyl) carbamic acid (9)H-fluoren-9-yl) methyl ester. The crude product was used without further purification in the subsequent step: c₃₂H₂₉Cl₂F₃N₂O₄ [M + H]⁺Calculated lcms (esi): 633, 635 (3: 2), found 633, 635 (3: 2).

Step e:

to a stirred ((2- (allyloxy) -4, 5-dichlorophenyl) (1- (2,2, 2-trifluoroacetyl) piperidin-4-yl) methyl) carbamic acid (9) at room temperatureHTo a solution of-fluoren-9-yl) methyl ester (crude) in DCM (2 mL) was added diethylamine (55 mg, 0.76 mmol). The reaction solution was stirred at room temperature for 16 hours. The resulting solution was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 55% aqueous ACN to give 1- (4- [ amino [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl) as a brown oil ]Methyl radical]Piperidin-1-yl) -2,2, 2-trifluoroethyl-1-one (70 mg, 58% of the two steps in total) C₁₇H₁₉Cl₂F₃N₂O₂ [M + H]⁺Calculated lcms (esi): 411, 413 (3: 2), found 411, 413 (3: 2).

Step f:

to a stirred 1- (4- [ amino [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl group at room temperature under a nitrogen atmosphere]Methyl radical]Piperidin-1-yl) -2,2, 2-trifluoroethyl-1-oneKetone (70 mg, 0.17 mmol) and Pd (PPh)₃)₄(4 mg, 0.003 mmol) in THF (2 mL) NaBH was added₄(8 mg, 0.20 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The resulting mixture was quenched with water (5 mL) at room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 36% B to 46% B in 7 minutes; a detector: UV 254/210 nm; retention time: 4.90 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 77 (1- [4- [ amino (4, 5-dichloro-2-hydroxyphenyl) methyl) as an off-white solid]Piperidin-1-yl radical]-2,2, 2-trifluoroethyl-1-one-trifluoroacetic acid) (10 mg, 16%): C₁₄H₁₅Cl₂F₃N₂O₂ [M + H]⁺Lcms (esi) calculated value of (a): 371, 372 (3: 2), found 371, 372 (3: 2); ¹H NMR (300 MHz, CD₃OD) δ 7.45 (s, 1H), 7.00 (s, 1H), 5.08 (d, J = 10.3 Hz, 1H), 3.54-3.43 (m, 2H), 3.13-2.86 (m, 2H), 2.31-2.05 (m, 2H), 1.63-1.45 (m, 3H)。

Example 144 Compound 79 ((4- ((s) (4)S) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) ((s)S) -pyrrolidin-3-yl-methanone) and compound 85 ((4- ((4: (a)R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) ((S) -pyrrolidin-3-yl) methanone

Step a:

(4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl)(s) were separated by chiral preparative HPLC under the following conditionsS) -pyrrolidin-3-yl) methanone (free base of compound 63, example 131) (50 mg) column: CHIRALPAK IG UL001, 20X 250 mm, 5 μm; mobile phase A: hexane (0.3% IPA), mobile phase B: EtOH; flow rate: 20 mL/min; gradient: from 40% B to 40% B in 22 minutes; a detector: UV 254/220 nm; health-care productRetention time: RT (reverse transcription)₁14.492 minutes; RT (reverse transcription)₂19.856 minutes; the injection volume was 0.6 ml.

The faster eluting enantiomer was obtained as compound 79 as an off-white solid at 14.492 min ((4- ((s) (4)S) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) ((S) -pyrrolidin-3-yl) methanone) (26.1 mg, 52%): C₁₇H₂₃Cl₂N₃O₂ [M + H]⁺Calculated lcms (esi): 372, 374 (3: 2), measured 372, 374 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.21 (d, J = 3.8 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 4.56 (dd, J = 28.0, 13.2 Hz, 1H), 4.10 (dd, J = 28.9, 13.7 Hz, 1H), 3.96-3.83 (m, 1H), 3.30-3.25 (m, 1H), 3.19-2.83 (m, 5H), 2.70-2.49 (m, 1H), 2.15-1.82 (m, 4H), 1.61-1.06 (m, 3H)。

the slower eluting enantiomer was obtained as compound 85 ((4- ((s) (b) in the form of an off-white solid) at 19.856 minutes R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) ((S) -pyrrolidin-3-yl) methanone) (8.2 mg, 16%): C₁₇H₂₃Cl₂N₃O₂ [M + H]⁺Calculated lcms (esi): 372, 374 (3: 2), measured 372, 374 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.21 (d, J = 3.8 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 4.56 (dd, J = 28.0, 13.2 Hz, 1H), 4.10 (dd, J = 28.9, 13.7 Hz, 1H), 3.96-3.83 (m, 1H), 3.30-3.25 (m, 1H), 3.19-2.83 (m, 5H), 2.70-2.49 (m, 1H), 2.15-1.82 (m, 4H), 1.61-1.06 (m, 3H)。

example 145 Compound 83 (2- [ (2- [))R) -amino [1- (azetidine-3-carbonyl) piperidin-4-yl]Methyl radical]-4, 5-dichlorophenol trifluoroacetic acid)

Step a:

stirring under nitrogen atmosphere at room temperatureS)-N-((R) - (2- (C)-2-en-1-yloxy) -4, 5-dichlorophenyl) (piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (intermediate 6, example 6) (0.50 g, 1.19 mmol) and 1- [ (tert-butoxy) carbonyl]A solution of azetidine-3-carboxylic acid (0.72 g, 3.58 mmol) in DMF (5 mL) was added in portions to Et₃N (0.37 g, 3.66 mmol) and EDCI (0.68 g, 3.54 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction was quenched with water (50 mL) at room temperature and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC, eluting with PE/EA (5/1) to give 3- (4- ((5/1) as a yellow solidR) - (2- (prop-2-en-1-yloxy) -4, 5-dichlorophenyl) (( S) -1, 1-Dimethylethylsulfenamide) methyl) piperidine-1-carbonyl) azetidine-1-carboxylic acid tert-butyl ester (0.39 g, 54%)₂₈H₄₁Cl₂N₃O₅S [M + H]⁺Calculated lcms (esi): 602, 604 (3: 2), measured values 602, 604 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.45 (d, J = 1.9 Hz, 1H), 7.18 (d, J = 1.6 Hz, 1H), 6.17-6.03 (m, 1H), 5.50-5.40 (m, 1H), 5.39-5.30 (m, 1H), 4.68-4.55 (m, 2H), 4.46 (d, J = 13.2 Hz, 1H), 4.13-4.03 (m, 5H), 3.80-3.54 (m, 2H), 3.10-2.90 (m, 1H), 2.72-2.53 (m, 1H), 2.24-2.13 (m, 1H), 2.08-2.01 (m, 1H), 1.41 (s, 9H), 1.40-1.17 (m, 3H), 1.14 (d, J = 2.0 Hz, 9H)。

step b:

to stirred 3- (4- ((C) at room temperature under nitrogen atmosphereR) - (2- (prop-2-en-1-yloxy) -4, 5-dichlorophenyl) ((S) -1, 1-Dimethylethylsulfenamide) methyl) piperidine-1-carbonyl) azetidine-1-carboxylic acid tert-butyl ester (0.39 g, 0.65 mmol) and Pd (PPh)₃)₄(15 mg, 0.01 mmol) in THF (8 mL) NaBH was added₄(37 mg, 0.97 mmol). The resulting mixture was stirred at room temperature under nitrogen for 40 minutes. The reaction was quenched with water (20 mL) and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄Dried and filtered. Concentrating the filtrate under reduced pressure to obtain 3- (4- ((4)R) - (4, 5-dichloro-2-hydroxyphenyl) ((S) -1, 1-Dimethylethylsulfenamide) methyl) piperidine-1-carbonyl) azetidine-1-carboxylic acid tert-butyl ester (0.34 g, crude), which was used without further purification in the subsequent step C₂₅H₃₇Cl₂N₃O₅S [M + H]⁺Calculated lcms (esi): 562, 564 (3: 2), found 562, 564 (3: 2).

Step c:

to stirred 3- (4- ((s) (C)R) - (4, 5-dichloro-2-hydroxyphenyl) ((S) (iv) -1, 1-Dimethylethylsulfonamido) methyl) piperidine-1-carbonyl) azetidine-1-carboxylic acid tert-butyl ester (0.34 g, 0.65 mmol) in 1, 4-dioxane (3 mL) was added aqueous HCl (4. mu.L) solutionN3 mL). The reaction solution was stirred at room temperature for 1 hour. Concentrating the obtained solution under reduced pressure to obtain crude 3- [4- [ (S) ((S) ()) in the form of dark yellow solidR) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]Azetidine-1-carboxylic acid tert-butyl ester, which is used directly in the subsequent step without further purification C₂₁H₂₉Cl₂N₃O₄ [M + H]⁺Calculated lcms (esi): 458, 460 (3: 2), found 458, 460 (3: 2).

Step d:

stirring 3- [4- [ (ii) at room temperatureR) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]To a solution of azetidine-1-carboxylic acid tert-butyl ester (crude) in DCM (3 mL) was added TFA (1 mL). The reaction solution was stirred at room temperature for 30 minutes. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: x Bridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 2% B to 30% B in 6 minutes; a detector: UV 254/210 nm; retention time: 4.94 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 83 (2- [ (2-)) as an off-white solid R) -amino [1- (azetidine-3-carbonyl) piperidin-4-yl]Methyl radical]-4, 5-dichlorophenol trifluoroacetic acid) (0.11 g, 36% of the total of the three steps) C₁₆H₂₁Cl₂N₃O₂ [M + H]⁺Calculated lcms (esi): 358, 360 (3: 2), found 358, 360 (3: 2); ¹H NMR (400 MHz, CD₃OD) δ 7.22 (d, J = 6.0 Hz, 1H), 6.86 (d, J = 4.0 Hz, 1H), 4.54 (dd, J = 38.1, 13.4 Hz, 1H), 4.39-3.95 (m, 6H), 3.62 (dd, J = 37.6, 13.8 Hz, 1H), 3.10-2.86 (m, 1H), 2.42-2.28 (m, 1H), 2.16-1.91 (m, 1H), 1.56-1.41 (m, 2H), 1.31-1.06 (m, 1H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.02.

in a manner analogous to that described for compound 83, fromS)-N-((R) Starting with- (2- (allyloxy) -4, 5-dichlorophenyl) (piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide and the corresponding acid (which is prepared as described herein or is available from commercial sources), the compounds in table 1a below are prepared.

TABLE 1a

Example 146 Compound 80 ((4- ((4: (a)R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) ((R) -pyrrolidin-3-yl) methanone); compound 84 ((4- ((s))S) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) ((R) -pyrrolidin-3-yl) methanone

Step a:

(4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl)(s) were separated by chiral preparative HPLC under the following conditionsR) -pyrrolidin-3-yl) methanone (free base of compound 66, example 134) (120 mg): column: CHIRALPAK IG UL001, 20X 250 mm, 5 μm; mobile phase A: hexane (0.1% IPA), mobile phase B: EtOH; flow rate: 16 mL/min; gradient: from 50% B to 50% B in 20 minutes; a detector: UV 254/220 nm; retention time: RT (reverse transcription) ₁11.704 minutes; RT (reverse transcription)₂17.496 minutes; the injection volume is 1 mL.

The faster eluting enantiomer was obtained as compound 80 in the form of an off-white solid at 14.492 min ((4- ((s) (b))R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) ((s)R) -pyrrolidin-3-yl) methanone) (35.8 mg, 30%): C₁₇H₂₃Cl₂N₃O₂ [M + H]⁺Calculated lcms (esi): 372, 374 (3: 2), measured 372, 374 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.22 (d, J = 4.4 Hz, 1H), 6.86 (d, J = 2.8 Hz, 1H), 4.56 (dd, J = 27.3, 12.2 Hz, 1H), 4.11 (dd, J = 13.6, 28.5 Hz, 1H), 3.94-3.86 (m, 1H), 3.30-3.25 (m, 1H), 3.19-2.88 (m, 5H), 2.68-2.48 (m, 1H), 2.23-1.85 (m, 4H), 1.54-1.06 (m, 3H)。

the slower eluting enantiomer was obtained as compound 84 ((4- ((s) (b)) as an off-white solid at 19.856 minutesS) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) ((R) -pyrrolidin-3-yl) methanone) (37.4 mg, 31%): C₁₇H₂₃Cl₂N₃O₂ [M + H]⁺Calculated lcms (esi): 372, 374 (3: 2), measured 372, 374 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.22 (d, J = 4.4 Hz, 1H), 6.86 (d, J = 2.8 Hz, 1H), 4.56 (dd, J = 27.3, 12.2 Hz, 1H), 4.11 (dd, J = 13.6, 28.5 Hz, 1H), 3.94-3.86 (m, 1H), 3.30-3.25 (m, 1H), 3.19-2.88 (m, 5H), 2.68-2.48 (m, 1H), 2.23-1.85 (m, 4H), 1.54-1.06 (m, 3H)。

EXAMPLE 147 Compound 86 (2- [ amino (piperidin-4-yl) methyl ] -3, 4-dichlorophenol bis (trifluoroacetic acid)

Step a:

will be provided withN- [ (2, 3-dichloro-6-hydroxyphenyl) (pyridin-4-yl) methyl]Acetamide (intermediate 64, example 64) (0.20 g, 0.65 mmol) in aqueous HCl (6)N6 mL) was stirred at 100 ℃ for 30 minutes. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure to give 2- [ amino (pyridin-4-yl) methyl ] as a pale yellow solid]-3, 4-dichlorophenol (0.16 g, crude), which was used in the next step without further purification. C ₁₂H₁₀Cl₂N₂O [M + H]⁺Lcms (esi) calculated value of (a): 269, 271 (3: 2), found 269, 271 (3: 2).

Step b:

to 2- [ amino (pyridin-4-yl) methyl at room temperature]To a solution of (0.16 g, 0.60 mmol) of (3, 4-dichlorophenol in MeOH (7 mL) was added PtO₂(30 mg, 0.13 mmol). The mixture was stirred at 30 ℃ for 5 hours under a hydrogen atmosphere (50 atm). The reaction was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100 mm, 10 μm, 19 mm × 250 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 8% B to 38% B in 6.5 minutes; a detector: UV 254/210 nm; retention time: 5.18 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure to give compound 8 as a purple solid6- (2- [ amino (piperidin-4-yl) methyl)]-3, 4-dichlorophenol bis (trifluoroacetic acid)) (25 mg, 8% two-step total): C₁₂H₁₆Cl₂N₂O [M + H]⁺Calculated lcms (esi): 275, 277 (3: 2), found 275, 277 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.49 (dd, J = 8.9, 1.3 Hz, 1H), 6.95 (d, J = 8.9 Hz, 1H), 4.73 (d, J = 10.0 Hz, 1H), 3.55 (d, J = 13.0 Hz, 1H), 3.39 (d, J = 13.0 Hz, 1H), 3.06 (td, J = 13.1, 3.1 Hz, 1H), 2.94 (td, J = 12.4, 4.5 Hz, 1H), 2.80-2.63 (m, 1H), 2.33-2.22 (m, 1H), 1.76-1.63 (m, 1H), 1.63-1.46 (m, 2H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.00 (d, J = 3.0 Hz)。

EXAMPLE 148 Compound 92 (2-amino-1- [4- [ (()R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidin-1-yl radical]Eth-1-one trifluoroacetic acid

Step a:

to a stirred solution of 2- ((tert-butoxycarbonyl) amino) acetic acid (0.30 g, 1.74 mmol) and HATU (0.66 g, 1.74 mmol) in DMF (5 mL) at room temperature under a nitrogen atmosphere was added: (C.) ( S)-N-((R) - (2- (allyloxy) -4, 5-dichlorophenyl) (piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (0.25 g, 0.58 mmol) and Et₃N (0.18 g, 1.74 mmol). The reaction solution was stirred at room temperature under nitrogen atmosphere for 3 hours. The resulting solution was quenched with water (40 mL) and extracted with EA (3X 50 mL). The combined organic layers were washed with water (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with a solution containing 10 mmol/L NH₄HCO₃Is eluted with 70% aqueous ACN solution to obtain (2- (4- ((or) (a) is obtained) as a yellow oilR) - (2- (allyloxy) -4, 5-dichlorophenyl) ((S) -1, 1-Dimethylethylsulfenamide) methyl) piperidin-1-yl) -2-oxoethyl) carbamic acid tert-butyl ester (0.19 g, 54%)₂₆H₃₉Cl₂N₃O₅S [M + H]⁺Calculated lcms (esi): 576, 578 (3: 2), found 576, 578 (3: 2);¹H NMR (300 MHz, CDCl₃) δ 7.22 (d, J = 5.1 Hz, 1H), 6.98 (s, 1H), 6.13-6.01 (m, 1H), 5.54-5.29 (m, 4H), 4.65-4.52 (m, 3H), 4.49 (s, 2H), 3.94-3.80 (m, 2H), 3.08-2.82 (m, 1H), 2.64-2.39 (m, 1H), 2.14-1.95 (m, 2H), 1.57-1.19 (m, 3H), 1.47 (s, 9H), 1.16 (s, 9H)。

step b:

stirring (2- (4- ((c) under nitrogen atmosphere) at room temperatureR) - (2- (allyloxy) -4, 5-dichlorophenyl) ((S) -1, 1-Dimethylethylsulfenamide) methyl) piperidin-1-yl) -2-oxoethyl) carbamic acid tert-butyl ester (0.19 g, 0.33 mmol) and Pd (PPh)₃)₄(33 mg, 0.03 mmol) in THF (5 mL) NaBH was added₄(19 mg, 0.50 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. The resulting mixture was quenched with water (50 mL) at room temperature and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give crude (2- (4- (4) ((b))R) - (4, 5-dichloro-2-hydroxyphenyl) ((S) -1, 1-dimethylethylenesulfonamido) methyl) piperidin-1-yl) -2-oxoethyl) carbamic acid tert-butyl ester. The crude product was used without further purification in the subsequent step: c₂₃H₃₅Cl₂N₃O₅S [M + H]⁺Calculated lcms (esi): 536, 538 (3: 2), found 536, 538 (3: 2).

Step c:

stirring (2- (4-(s) at room temperatureR) - (4, 5-dichloro-2-hydroxyphenyl) ((S) -1, 1-Dimethylethylsulfonamido) methyl) piperidin-1-yl) -2-oxoethyl) carbamic acid tert-butyl ester (crude) solution in 1, 4-dioxane (5 mL) was added aqueous HCl (6)N3 mL). The reaction solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure. The residue was dissolved in DCM (6 mL), and TFA (3 mL) was added at room temperature. The reaction solution was stirred at room temperature for another 1 hour. Mixing the obtained solutionConcentrating under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: SunAire C18 OBD Prep Column, 100A, 5 μm, 19 mm × 250 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 10% B to 13% B in 6 minutes; a detector: UV 210 nm; retention time: 5.57 minutes. Collecting the fractions containing the desired product, concentrating under reduced pressure to obtain compound 92 (2-amino-1- [4- [ (2-amino-1- [ 4-)) as an off-white solid R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidin-1-yl radical]Ethan-1-one trifluoroacetic acid) (20 mg, 14% two-step total): C₁₄H₁₉Cl₂N₃O₂ [M + H]⁺Lcms (esi) calculated value of (a): 332, 334 (3: 2), found 332, 334 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.20 (s, 1H), 6.86 (s, 1H), 4.55 (dd, J = 35.7, 13.5 Hz, 1H), 3.93-3.74 (m, 2H), 3.45 (dd, J = 10.9, 3.7 Hz, 2H), 3.08-2.85 (m, 1H), 2.70-2.56 (m, 1H), 2.10-1.94 (m, 2H), 1.58-1.46 (m, 1H), 1.34-1.10 (m, 2H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.04。

in a manner analogous to that described for Compound 92, fromS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]Starting with 2-methylpropane-2-sulfinamide and the corresponding acid (which is prepared as described herein, or is available from a commercial source), the compounds in table 1b below are prepared.

TABLE 1b

EXAMPLE 149 Compound 101 (4, 5-dichloro-2- [ hydroxy ([1- [ (3) amino)R) -pyrrolidine-3-carbonyl]Piperidin-4-yl radical]) Methyl radical]Phenol); compound 116 (4, 5-dichloro-2- [ (s))R) -hydroxy ([1- [ (3)R) -pyrrolidine-3-carbonyl]Piperidin-4-yl radical]) Methyl radical]Phenol); and compound 115 (4, 5-dichloro-2- [ (s))S) -hydroxy ([1- [ (3)R) -pyrrolidine-3-carbonyl]Piperidin-4-yl radical]) Methyl radical]Phenol)

Step a:

to a stirred solution of tert-butyl 4- (4, 5-dichloro-2-hydroxybenzoyl) piperidine-1-carboxylate (0.80 g, 2.14 mmol) in DCM (2 mL) was added TFA (2 mL, 26.93 mmol) at room temperature. After stirring at room temperature for 1 hour, the resulting mixture was concentrated under reduced pressure. The crude product was used directly in the subsequent step without further purification. C ₁₂H₁₃Cl₂NO₂ [M + H]⁺Lcms (esi) calculated value of (a): 274, 276 (3: 2), found 274, 276 (3: 2).

Step b:

to CDI (0.25 g, 1.57 mmol) and (3) at room temperature under nitrogen atmosphereR) -1- [ (tert-butoxy) carbonyl]To a solution of pyrrolidine-3-carboxylic acid (0.39 g, 1.80 mmol) in DMF 2 (mL) was added a solution of 4, 5-dichloro-2- (piperidine-4-carbonyl) phenol trifluoroacetic acid (0.10 g, 0.26 mmol) in DMF (2 mL) and Et₃N (1.10 g, 10.87 mmol). The reaction solution was stirred at room temperature for an additional 2 hours. The resulting mixture was diluted with water (50 mL) and extracted with EA (3X 10 mL) at room temperature. The combined organic layers were washed with brine (3X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (1:1) to give (3) as an off-white solidR) -3- [4- (4, 5-dichloro-2-hydroxybenzoyl) piperidine-1-carbonyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (0.11 g, 88%): C₂₂H₂₈Cl₂N₂O₅ [M + H]⁺Calculated lcms (esi): 471, 473 (3: 2), found 471, 473 (3: 2).

Step c:

stirring at room temperature (3)R) -3- [4- (4, 5-dichloro-2-hydroxybenzoyl) piperidine-1-carbonyl]To a solution of pyrrolidine-1-carboxylic acid tert-butyl ester (0.15 g, 0.24 mmol) in DCM (2 mL) was added TFA (2 mL). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was used without further purification in the subsequent step: c ₁₇H₂₀Cl₂N₂O₃ [M + H]⁺Lcms (esi) calculated value of (a): 371, 373 (3: 2), found 371, 373 (3: 2).

Step d:

stirring 4, 5-dichloro-2- [1- [ (3) at room temperature under air atmosphereR) -pyrrolidine-3-carbonyl]Piperidine-4-carbonyl]To a solution of phenol (80 mg, 0.22 mmol) in MeOH (3 mL) was added NaBH₄(27.2 mg, 0.72 mmol). The resulting mixture was stirred at room temperature under nitrogen for 1.5 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column, 100A, 10 μm, 19 mm × 250 mm; mobile phase A: having a NH concentration of 10 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 5% B to 80% B in 6 minutes; a detector: UV 254/210 nm; retention time: 5.43 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 101 (4, 5-dichloro-2- [ hydroxy ([1- [ (3) as an off-white solidR) -pyrrolidine-3-carbonyl]Piperidin-4-yl radical]) Methyl radical]Phenol) (55 mg, 64%): C₁₇H₂₂Cl₂N₂O₃ [M + H]⁺Calculated lcms (esi): 373, 375 (3: 2), found 373, 375 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.35 (d, J = 1.6 Hz, 1H), 6.88 (s, 1H), 4.74 (t, J = 5.4 Hz, 1H), 4.54 (s, 1H), 4.09 (t, J = 13.1 Hz, 1H), 3.31-3.25 (m, 1H), 3.18-2.83 (m, 5H), 2.58 (t, J = 12.8 Hz, 1H), 2.20-1.81 (m, 4H), 1.53 (t, J = 14.1 Hz, 1H), 1.44-1.19 (m, 2H)。

step e:

separation of 4, 5-dichloro-2- [ hydroxy ([1- [ (3) by chiral preparative HPLC under the following conditionsR) -pyrrolidine-3-carbonyl ]Piperidin-4-yl radical]) Methyl radical]Phenol (55 mg, 0.14 mmol) column: chiralpak IC, 2X 25 cm, 5 μm; mobile phase A: hexane (0.2% IPA), mobile phase B: EtOH; flow rate: 20 mL/min; gradient: from 20% B to 20% B in 26 minutes; a detector: UV 220 nm; retention time: RT (reverse transcription)₁14.035 minutes; RT (reverse transcription)₂20.088 minutes; the temperature is 25 ℃.

The faster eluting enantiomer was obtained as compound 116 (4, 5-dichloro-2- [(s) (s)) as an off-white solid at 14.035 minutesR) -hydroxy ([1- [ (3)R) -pyrrolidine-3-carbonyl]Piperidin-4-yl radical]) Methyl radical]Phenol) (10 mg, 18%) C₁₇H₂₂Cl₂N₂O₃ [M + H]⁺Calculated lcms (esi): 373, 375 (3: 2), found 373, 375 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.35 (d, J = 1.6 Hz, 1H), 6.88 (s, 1H), 4.74 (t, J = 5.4 Hz, 1H), 4.54 (s, 1H), 4.09 (t, J = 13.1 Hz, 1H), 3.31-3.25 (m, 1H), 3.18-2.83 (m, 5H), 2.58 (t, J = 12.8 Hz, 1H), 2.20-1.81 (m, 4H), 1.53 (t, J =14.1 Hz, 1H), 1.44-1.19 (m, 2H)。

the slower eluting enantiomer was obtained as compound 115 (4, 5-dichloro-2- [ () ] as an off-white solid at 20.088 minutesS) -hydroxy ([1- [ (3)R) -pyrrolidine-3-carbonyl]Piperidin-4-yl radical]) Methyl radical]Phenol) (21 mg, 21%) C₁₇H₂₂Cl₂N₂O₃ [M + H]⁺Calculated lcms (esi): 373, 375 (3: 2), found 373, 375 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.35 (d, J = 1.6 Hz, 1H), 6.88 (s, 1H), 4.74 (t, J = 5.4 Hz, 1H), 4.54 (s, 1H), 4.09 (t, J = 13.1 Hz, 1H), 3.31-3.25 (m, 1H), 3.18-2.83 (m, 5H), 2.58 (t, J = 12.8 Hz, 1H), 2.20-1.81 (m, 4H), 1.53 (t, J =14.1 Hz, 1H), 1.44-1.19 (m, 2H)。

example 150 Compound 102 (, (S)-1-(4-((R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) -2-hydroxypropan-1-one

Step a:

stirring under nitrogen atmosphere at room temperatureS) -2-Hydroxypropionic acid (0.19 g, 2.16 mmol) and Et ₃To a solution of N (0.22 g, 2.16 mmol) in DMF (3 mL) was added CDI (0.29 g, 2.09 mmol) in portions. After stirring at room temperature for 1 hour under a nitrogen atmosphere, (ii) AS)-N-((R) A solution of (2- (allyloxy) -4, 5-dichlorophenyl) (piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (0.30 g, 0.72 mmol) in DMF (1 mL) was added dropwise to the resulting solution. After the addition, the reaction solution was stirred at room temperature for another 12 hours under a nitrogen atmosphere. The resulting solution was diluted with water (50 mL) at room temperature and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC, eluting with PE/EA (1/3), to give (A) as a yellow solidS)-N-((R) - (2- (allyloxy) -4, 5-dichlorophenyl) (1- ((S) -2-hydroxypropionyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (0.10 g, 29%): C₂₂H₃₂Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 491, 493 (3: 2), found 491, 493 (3: 2).

Step b:

stirring under nitrogen atmosphere at room temperatureS)-N-((R) - (2- (allyloxy) -4, 5-dichlorophenyl) (1- ((S) -2-hydroxypropionyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (0.10 g, 0.20 mmol) and Pd (PPh) ₃)₄(22 mg, 0.02 mmol) in THF (4 mL) was added NaBH₄(11 mg, 0.30 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The resulting mixture was quenched with water (40 mL) at room temperature and extracted with EA (3X 40 mL). The combined organic layers were washed with brine (3X 20 m)L) washing, passing through anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give crude product (A)S)-N-((R) - (4, 5-dichloro-2-hydroxyphenyl) (1- ((2)S) -2-hydroxypropionyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide. The crude product was used without further purification in the subsequent step: c₁₉H₂₈Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 451, 453 (3: 2), found 451, 453 (3: 2).

Step c:

stirring at room temperature (S)-N-((R) - (4, 5-dichloro-2-hydroxyphenyl) (1- ((2)S) (ii) -2-hydroxypropionyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (crude) to a solution in 1, 4-dioxane (5 mL) was added aqueous HCl (6)N3 mL). The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column, 100A, 10 μm, 19 mm × 250 mm; mobile phase A: having a NH concentration of 10 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 20% B to 50% B in 6 minutes; a detector: UV 254/210 nm; retention time: 5.58 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 102 as an off-white solid (, (R) (R)) S)-1-(4-((R) Amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) -2-hydroxypropan-1-one) (10.0 mg, 14% of the total of the two steps) C₁₅H₂₀Cl₂N₂O₃[M + H]⁺Lcms (esi) calculated value of (a): 347, 349 (3: 2), found 347, 349 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 6.88 (s, 1H), 4.63-4.46 (m, 2H), δ 4.04 (dd, J = 13.8, 35.1 Hz, 1H), 3.90 (t, J = 6.5 Hz, 1H), 3.12-2.93 (m, 1H), 2.74-2.51 (m, 1H), 2.10-1.90 (m, 2H), 1.50 (d, J = 13.4 Hz, 1H), 1.31 (d, J = 6.6 Hz, 3H), 1.32-1.08 (m, 2H)。

example 151 Compound 104 (2- [ () (R) -amino ([1- [ (3)R) -1-methylpyrrolidine-3-carbonyl]Piperidin-4-yl radical]) Methyl radical]-4,5-dichlorophenol)

Step a:

stirring 4- [ (ii) (b) at room temperature under nitrogen atmosphereR) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester (0.25 g, 0.48 mmol) and Pd (PPh)₃)₄(6 mg, 0.005 mmol) in THF (2 mL) NaBH was added₄(36 mg, 0.96 mmol). After stirring at room temperature for 1 hour under nitrogen atmosphere, the resulting mixture was quenched with water (2 mL) at room temperature and concentrated under reduced pressure. The residue was purified by reverse phase chromatography with 20% NH₄HCO₃Eluted with 70% aqueous MeOH to give 4- [ (iii) as a yellow oilR) - (4, 5-dichloro-2-hydroxyphenyl) [ (2-methylpropane-2-sulfinyl) amino]Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester (0.15 g, 65%): C₂₁H₃₂Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 479, 481 (3: 2), found 479, 481 (3: 2).

Step b:

4- [ (ii) to stirring at room temperature R) - (4, 5-dichloro-2-hydroxyphenyl) [ (2-methylpropane-2-sulfinyl) amino]Methyl radical]To a solution of tert-butyl piperidine-1-carboxylate (0.15 g, 0.31 mmol) in DCM (2 mL) was added TFA (0.5 mL). The reaction solution was stirred at room temperature for 30 minutes. The resulting solution was taken up in saturated NaHCO₃The aqueous solution was neutralized to pH 8 and concentrated under reduced pressure. The residue was purified by washing with a solution having 10% NH₄HCO₃Is purified by reverse phase chromatography in 50% aqueous ACN solution to obtain a yellow oilN-[(R) - (4, 5-dichloro-2-hydroxyphenyl) (piperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide (80 mg, 67%): C₁₆H₂₄Cl₂N₂O₂S [M + H]⁺Calculated lcms (esi): 379, 381 (3: 2), found 379, 381 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.18 (s, 1H), 6.83 (s, 1H), 4.26 (d, J = 8.8 Hz, 1H), 3.20 (d, J = 12.7 Hz, 1H), 3.04 (d, J = 12.7 Hz, 1H), 2.76-2.51 (m, 2H), 2.21 (d, J = 13.8 Hz, 1H), 2.08-1.90 (m, 1H), 1.48-1.23 (m, 3H), 1.14 (s, 9H)。

step c:

to stirred EDCI (61 mg, 0.32 mmol) and (3) at room temperature under nitrogenR) Et was added to a solution of (1-methylpyrrolidine-3-carboxylic acid) (25 mg, 0.19 mmol) in DMF (2 mL)₃N (32 mg, 0.32 mmol) and N- [ (S) ((S))R) - (4, 5-dichloro-2-hydroxyphenyl) (piperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide (60 mg, 0.16 mmol). After stirring at room temperature for 16 hours under nitrogen atmosphere, the resulting solution was quenched with water (30 mL) and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give a crude product N-((R) - (4, 5-dichloro-2-hydroxyphenyl) (1- ((2)R) -1-methylpyrrolidine-3-carbonyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide. The crude product was used without further purification in the subsequent step: c₂₂H₃₃Cl₂N₃O₃S [M + H]⁺Calculated lcms (esi): 490, 492 (3: 2), found 490, 492 (3: 2).

Step d:

at room temperature with stirringN-((R) - (4, 5-dichloro-2-hydroxyphenyl) (1- ((2)R) (ii) -1-methylpyrrolidine-3-carbonyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (crude) to a solution in 1, 4-dioxane (2 mL) was added aqueous HCl (6)N1 mL). The reaction solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase A: having a NH concentration of 10 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 30% B to 80% B in 6 minutes; a detector: UV 254/210 nm; retention time: 4.42 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 104 (2- [ (2-)) as an off-white solidR) -amino ([1- [ (3)R) -1-methylpyrrolidine-3-carbonylBase of]Piperidin-4-yl radical]) Methyl radical]-4, 5-dichlorophenol) (13 mg, 33% of two steps in total): C ₁₈H₂₅Cl₂N₃O₂[M + H]⁺Lcms (esi) calculated value of (a): 386, 388 (3: 2), found 386, 388 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.22 (s, 1H), 6.87 (s, 1H), 4.57 (dd, J = 29.1, 13.3 Hz, 1H), 4.03 (dd, J = 27.8, 13.8 Hz, 1H), 3.90 (t, J = 7.2 Hz, 1H), 3.35-3.30 (m, 1H), 3.16-2.86 (m, 2H), 2.84-2.51 (m, 4H), 2.45-2.39 (m, 3H), 2.21-1.90 (m, 4H), 1.57-1.07 (m, 3H)。

example 152 Compound 105 (, (R)-1-(4-((R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) -2-hydroxypropan-1-one

Step a:

stirring under nitrogen atmosphere at room temperatureR) -2-Hydroxypropionic acid (86 mg, 0.96 mmol) and Et₃To a solution of N (97 mg, 0.95 mmol) in DMF (3 mL) was added CDI (0.15 g, 0.95 mmol) in portions. After stirring at room temperature for 1 hour under a nitrogen atmosphere, (ii) AS)-N-((R) A solution of (2- (allyloxy) -4, 5-dichlorophenyl) (piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (0.20 g, 0.48 mmol) in DMF (1 mL) was added dropwise to the resulting solution. After the addition, the reaction solution was stirred at room temperature for another 12 hours under a nitrogen atmosphere. The resulting solution was diluted with water (50 mL) and extracted with EA (3X 40 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with 20% NH₄HCO₃Eluted with 60% ACN aqueous solution to obtain (A) as a yellow solidS)-N-((R) - (2- (allyloxy) -4, 5-dichlorophenyl) (1- ((3)R) -2-hydroxypropionyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (0.12 g, 46%): C ₂₂H₃₂Cl₂N₂O₄S [M + H]⁺Lcms (esi) calculated value of (a): 491, 493 (3: 2), found 491, 493 (3: 2);¹H NMR (400 MHz, CD₃OD): δ 7.45 (s, 1H), 7.18 (s, 1H), 6.18-5.96 (m, 1H), 5.52-5.30 (dd, J =44.4, 14.0 Hz, 2H), 4.70-4.62 (d, J = 5.2 Hz, 2H), 4.59-4.51 (m, 3H), 4.10 (dd, J = 55.6, 13.7 Hz, 1H), 3.15-2.87 (m, 1H), 2.75-2.57 (m, 1H), 2.30-2.00 (m, 2H), 1.52-1.20 (m, 6H), 1.10 (s, 9H)。

step b:

stirring under nitrogen atmosphere at room temperatureS)-N-((R) - (2- (allyloxy) -4, 5-dichlorophenyl) (1- ((3)R) -2-hydroxypropionyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (0.12 g, 0.19 mmol) and Pd (PPh)₃)₄(22 mg, 0.02 mmol) in THF (4 mL) NaBH was added₄(11 mg, 0.30 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. The resulting mixture was quenched with water (40 mL) at room temperature and extracted with EA (3X 40 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give crude product (A)S)-N-((R) - (4, 5-dichloro-2-hydroxyphenyl) (1- ((2)R) -2-hydroxypropionyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide. The crude product was used without further purification in the subsequent step: c₁₉H₂₈Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 451, 453 (3: 2), found 451, 453 (3: 2).

Step c:

stirring at room temperature (S)-N-((R) - (4, 5-dichloro-2-hydroxyphenyl) (1- ((2)R) (ii) -2-hydroxypropionyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (crude) to a solution in 1, 4-dioxane (5 mL) was added aqueous HCl (6) N3 mL). The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: atlantis HILIC OBD column, 19 × 150 mm, 5 μm; a mobile phase A: having a NH concentration of 10 mmol/L₄HCO₃Water +0.1% NH₃·H₂O, mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 30% B to 65% B in 6 minutes; a detector: UV 210 nm; retention time: 5.00 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 105 as an off-white solid (, (R) (R))R)-1-(4-((R) Amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) -2-hydroxypropan-1-one) (3.7 mg, 5% of two steps in total): C₁₅H₂₀Cl₂N₂O₃ [M + H]⁺Calculated lcms (esi): 347, 349 (3: 2), found 347, 349 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 6.88 (s, 1H), 4.63-4.46 (m, 2H), δ 4.04 (dd, J = 13.8, 35.1 Hz, 1H), 3.90 (t, J = 6.5 Hz, 1H), 3.12-2.93 (m, 1H), 2.74-2.51 (m, 1H), 2.10-1.90 (m, 2H), 1.50 (d, J = 13.4 Hz, 1H), 1.35-1.08 (m, 5H)。

example 153 Compound 106 ((4- ((4) (a)R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) ((S) -1-methylpyrrolidin-3-yl) methanone)

Step a:

stirring under nitrogen atmosphere at room temperatureS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.50 g, 1.19 mmol) and (3)S) -1- [ (tert-butoxy) carbonyl]Pyrrolidine-3-carboxylic acid (0.51 g, 2.38 mmol) in DMF (5 mL) was added Et ₃N (0.24 g, 2.38 mmol) and EDCI (0.46 g, 2.38 mmol). The reaction solution was stirred at room temperature under nitrogen atmosphere for 2 hours. The resulting solution was quenched with water (50 mL) at room temperature and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with a solution containing 10 mmol/L NH₄HCO₃Eluting with 10% -50% ACN water solution to obtain (3) as yellow solidS)-3-[4-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidine-1-carbonyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (0.35 g, 43%): C₂₉H₄₃Cl₂N₃O₅S [M + H]⁺Calculated lcms (esi): 616, 618 (3: 2), found 616, 618 (3: 2).

Step b:

stirring under nitrogen atmosphere at room temperatureS)-3-[4-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidine-1-carbonyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (0.30 g, 0.49 mmol) and Pd (PPh)₃)₄(11 mg, 0.01 mmol) in THF (5 mL) was added NaBH in portions₄(74 mg, 1.95 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The resulting mixture was quenched with water (40 mL) at room temperature and extracted with EA (3X 40 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography using a column containing 10 mmol/L NH₄HCO₃Eluting with 50% aqueous ACN solution to obtain (3) as yellow oilS) -3- [4- [ (4, 5-dichloro-2-hydroxyphenyl) [ (2-methylpropane-2-sulfinyl) amino]Methyl radical]Piperidine-1-carbonyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (0.20 g, 71%): C₂₆H₃₉Cl₂N₃O₅S [M + H]⁺Calculated lcms (esi): 576, 578 (3: 2), found 576, 578 (3: 2).

Step c:

stirring at room temperature (3)S) -3- [4- [ (4, 5-dichloro-2-hydroxyphenyl) [ (2-methylpropane-2-sulfinyl) amino]Methyl radical]Piperidine-1-carbonyl]A solution of pyrrolidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.35 mmol) in DCM (5 mL) was added TFA (1 mL) dropwise. The reaction solution was stirred at room temperature for 1 hour. Saturated NH for the resulting solution₄HCO₃The aqueous solution was neutralized at 0 ℃. The pH was adjusted to 7. The aqueous layer was extracted with EA (5X 50 mL). The combined organic layers were passed over anhydrous Na₂SO₄Dried and filtered. Will be provided withThe filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography using a column containing 20 mmol/L NH₄HCO₃Eluting with 40% ACN aqueous solution to obtain (A) as a yellow solidS)-N-((R) - (4, 5-dichloro-2-hydroxyphenyl) (1- ((2)S) -pyrrolidine-3-carbonyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (0.10 g, 39%): C ₂₁H₃₁Cl₂N₃O₃S [M + H]⁺Lcms (esi) calculated value of (a): 476, 478 (3: 2), found 476, 478 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.14 (d, J = 13.7 Hz, 1H), 7.01 (d, J = 13.3 Hz, 1H), 4.62 (dd, J = 50.6, 13.2 Hz, 1H), 4.31 (dd, J = 39.0, 7.8 Hz, 1H), 4.09-3.87 (m, 1H), 3.30-2.87 (m, 6H), 2.59 – 2.44 (m, 1H), 2.12 – 1.91 (m, 4H), 1.63-1.43 (m, 1H), 1.31-1.13 (m, 11H)。

step d:

to stirring (A)S)-N-((R) - (4, 5-dichloro-2-hydroxyphenyl) (1- ((2)S) -pyrrolidine-3-carbonyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (0.10 g, 0.21 mmol) and formaldehyde (9.5 mg, 0.32 mmol) in MeOH (2 mL) was added HOAc (13 mg, 0.21 mmol). After stirring at room temperature for 1 hour, NaBH (AcO) was added portionwise at room temperature₃(89 mg, 0.42 mmol). The reaction mixture was stirred at room temperature for an additional 1 hour. The resulting mixture was saturated with NH₄HCO₃The aqueous solution was neutralized and extracted with EA (5X 50 mL). The combined organic layers were concentrated under reduced pressure to give crude (A)S)-N-((R) - (4, 5-dichloro-2-hydroxyphenyl) (1- ((2)S) -1-methylpyrrolidine-3-carbonyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide. The crude product was used without further purification in the subsequent step: c₂₂H₃₃Cl₂N₃O₃S [M + H]⁺Calculated lcms (esi): 490, 492 (3: 2), found 490, 492 (3: 2).

Step e:

stirring at room temperature (S)-N-((R) - (4, 5-dichloro-2-hydroxyphenyl) (1- ((2)S) -1-methylpyrrolidine-3-carbonyl) piperidin-4-yl) methyl) -2-methylTo a solution of phenylpropane-2-sulfinamide (crude) in 1, 4-dioxane (2 mL) was added aqueous HCl (6) N, 1 mL). The reaction solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column, 100A, 5 μm, 19 mm × 250 mm; mobile phase A: having a NH concentration of 10 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 20% B to 80% B in 6 minutes; a detector: UV 254/210 nm; retention time: 4.72 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 106 as an off-white solid ((4- ((R) (C.))R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) ((S) -1-methylpyrrolidin-3-yl) methanone) (21.5 mg, 25% of two stages in total): C₁₈H₂₅Cl₂N₃O₂ [M + H]⁺Calculated lcms (esi): 386, 388 (3: 2), found 386, 388 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.22 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 1.1 Hz, 1H), 4.56 (dd, J = 28.9, 13.2 Hz, 1H), 4.03 (dd, J = 28.1, 13.7 Hz, 1H), 3.89 (t, J = 6.7 Hz, 1H), 3.30-3.23 (m, 1H), 3.14-2.88 (m, 2H), 2.81-2.46 (m, 4H), 2.44-2.32 (s, 3H), 2.20-1.94 (m, 4H), 1.62-1.03 (m, 3H)。

example 154 Compound 107 (2- [ (2- [))R) -amino [1- (azetidine-3-sulfonyl) piperidin-4-yl]Methyl radical]-4, 5-dichlorophenol)

Step a:

under nitrogen atmosphere at room temperature with stirringN-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.20 g, 0.48 mmol) and Et₃To a solution of N (97 mg, 0.96 mmol) in DCM (2 mL) was added tert-butyl 3- (chlorosulfonyl) azetidine-1-carboxylate (0.15 g, 0.59 mmol) in portions. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 hours. Will be described The resulting mixture was diluted with water (50 mL) and extracted with EA (3X 30 mL). The combined organic layers were washed with water (3X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC, eluted with PE/EA (5/1) to give 3- ([4- [ ((5/1) as an off-white solidR) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]Piperidin-1-yl radical]Sulfonyl) azetidine-1-carboxylic acid tert-butyl ester (0.12 g, 39%): C₂₇H₄₁Cl₂N₃O₆S₂ [M + H]⁺Calculated lcms (esi): 638, 640 (3: 2), found 638, 640 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.21 (s, 1H), 6.99 (s, 1H), 6.09-5.96 (m, 1H), 5.49-5.34 (m, 2H), 4.64-4.52 (m, 2H), 4.43 (s, 1H), 4.28-4.09 (m, 4H), 3.86 (d, J = 35.3 Hz, 3H), 2.73 (dd, J = 22.9, 11.6 Hz, 2H), 1.89 (s, 1H), 1.47 (s, 9H), 1.38-1.25 (m, 4H), 1.17 (s, 9H)。

step b:

to stirred 3- ([4- [ ((C) at room temperature under nitrogen atmosphereR) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]Piperidin-1-yl radical]Sulfonyl) azetidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.19 mmol) and Pd (PPh)₃)₄ (21 mg, 0.02 mmol) in THF (2 mL) NaBH was added portionwise₄(25 mg, 0.66 mmol). The resulting mixture was stirred at room temperature under nitrogen for 6 hours. The resulting mixture was quenched with water (40 mL) at room temperature and extracted with EA (3X 30 mL). The combined organic layers were washed with water (3X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC, eluted with PE/EA (5/1) to give 3- ([4- [ ((5/1) as a pale yellow solid R) - (4, 5-dichloro-2-hydroxyphenyl) [ (2-methylpropane-2-sulfinyl) amino]Methyl radical]Piperidin-1-yl radical]Sulfonyl) azetidine-1-carboxylic acid tert-butyl ester (80 mg, 71%): C₂₄H₃₇Cl₂N₃O₆S₂ [M + H]⁺Calculated lcms (esi): 598, 600 (3: 2), found 598, 600 (3: 2).

Step c:

stirring 3- ([4- [ (4- [)) at room temperatureR) - (4, 5-dichloro-2-hydroxyphenyl) [ (2-methylpropane-2-sulfinyl) amino]Methyl radical]Piperidin-1-yl radical]Sulfonyl) azetidine-1-carboxylic acid tert-butyl ester (80 mg, 0.15 mmol) in 1, 4-dioxane (5 mL) was added aqueous HCl (6 mL)N3 mL). The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was dissolved in DCM (6 mL), and TFA (3 mL) was added at room temperature. The reaction solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column, 100A, 10 μm, 19 mm × 250 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 20% B to 35% B in 12 minutes; a detector: 210 nm; retention time: 9.5 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure to give compound 107 (2- [ (2- [)) as an off-white solid R) -amino [1- (azetidine-3-sulfonyl) piperidin-4-yl]Methyl radical]-4, 5-dichlorophenol) (40 mg, 67%): C₁₅H₂₁Cl₂N₃O₃S [M + H]⁺Calculated lcms (esi): 394, 396 (3: 2), found 394, 396 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.22 (s, 1H), 6.86 (s, 1H), 4.37-4.26 (m, 1H), 4.01-3.87 (m, 3H), 3.87-3.65 (m, 4H), 2.86-2.63 (m, 2H), 2.10-1.76 (m, 2H), 1.56-1.15 (m, 3H)。

example 155 Compound 108(N- ((4, 5-dichloro-2-hydroxyphenyl) (1- ((2)R) -pyrrolidine-3-carbonyl) piperidin-4-yl) methyl) acetamide trifluoroacetic acid

Step a:

stirring at room temperature (3)R) -1- [ (tert-butoxy) carbonyl]EDCI (0.41 g, 2.15 mmol) was added to a mixture of pyrrolidine-3-carboxylic acid (0.46 g, 2.15 mmol) in DMF (2 mL). After stirring for 10 min, Et was added at room temperature₃N (0.43 g, 4.31 mmol) and N- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide (0.60 g, 1.44 mmol) was added to the resulting solution. The reaction solution was stirred at room temperature for another 16 hours. The resulting solution was diluted with water (40 mL) and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 75% aqueous ACN (plus 0.05% TFA) to give (3) as a pale yellow solidR) -3- (4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl)][ (2-methylpropane-2-sulfinyl) amino ]Methyl radical]Piperidine-1-carbonyl) pyrrolidine-1-carboxylic acid tert-butyl ester (0.40 g, 45%): C₂₉H₄₃Cl₂N₃O₅S [M + H]⁺Calculated lcms (esi): 616, 618 (3: 2), found 616, 618 (3: 2).

Step b:

stirring at room temperature (3)R) -3- (4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl)][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]To a solution of piperidine-1-carbonyl) pyrrolidine-1-carboxylic acid tert-butyl ester (0.40 g, 0.39 mmol) in 1, 4-dioxane (2 mL) was added aqueous HCl (4N0.67 mL). The reaction solution was stirred at room temperature for 30 minutes. The resulting solution was taken up in saturated NaHCO₃The aqueous solution adjusted the pH to 7. The resulting aqueous solution was extracted with EA (3X 50 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure to give (3) as a pale yellow solidR) -3- (4- [ amino [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]Piperidine-1-carbonyl) pyrrolidine-1-carboxylic acid tert-butyl ester (0.22 g, crude). C₂₅H₃₅Cl₂N₃O₄ [M + H]⁺Calculated lcms (esi): 512, 514 (3: 2), found 512, 514 (3: 2).

Step c:

stirring at room temperature (3)R) -3- (4- [ amino [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]Piperidine-1-carbonyl) pyrrolidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.39 mmol) and Et ₃N (0.13 g1.29 mmol) in DCM (2 mL) was added Ac₂O (88 mg, 0.86 mmol). The reaction solution was stirred at room temperature for 1 hour. The resulting solution was quenched with water (50 mL) at room temperature and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with EA to give (3) as an off-white solidR) -3- (4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl)](acetamido) methyl group]Piperidine-1-carbonyl) pyrrolidine-1-carboxylic acid tert-butyl ester (80 mg, 37% of two steps in total): C₂₇H₃₇Cl₂N₃O₅ [M + H]⁺Calculated lcms (esi): 554, 556 (3: 2), found 554, 556 (3: 2).

Step d:

under nitrogen atmosphere, at room temperature to (3)R) -3- (4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl)](acetamido) methyl group]Piperidine-1-carbonyl) pyrrolidine-1-carboxylic acid tert-butyl ester (80 mg, 0.14 mmol) and Pd (PPh)₃)₄ (3.3 mg, 0.002 mmol) in THF (2 mL) NaBH was added₄ (8.3 mg, 0.22 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. The resulting mixture was quenched with water (40 mL) at room temperature and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na ₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure to give (3) as a pale yellow solidR) -3- [4- [ (4, 5-dichloro-2-hydroxyphenyl) (acetamido) methyl group]Piperidine-1-carbonyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (74 mg, crude), which was used directly in the subsequent step without further purification. C₂₄H₃₃Cl₂N₃O₅ [M + H]⁺Lcms (esi) calculated value: 514, 516 (3: 2), found 514, 516 (3: 2).

Step e:

stirring at room temperature (3)R) -3- [4- [ (4, 5-dichloro-2-hydroxyphenyl) (acetamido) methyl group]Piperidine-1-carbonyl]To a solution of pyrrolidine-1-carboxylic acid tert-butyl ester (72 mg, 0.14 mmol) in DCM (1 mL) was added TFA (1 mL). The reaction solution was stirred at room temperature for 0.5 hour. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XSelect CSH Prep C18 OBD column, 5 μm, 19X 150 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 20% B to 30% B in 6 minutes; a detector: UV 210 nm; retention time: 4.60 minutes. The product containing fractions were collected and concentrated under reduced pressure to give compound 108 (b) as an off-white solidN- ((4, 5-dichloro-2-hydroxyphenyl) (1- ((2)R) -pyrrolidine-3-carbonyl) piperidin-4-yl) methyl) acetamide trifluoroacetic acid) (66 mg, 85% of a two-step total): C ₁₉H₂₅Cl₂N₃O₃ [M + H]⁺Lcms (esi) calculated: 414, 416 (3: 2), found 414, 416 (3: 2).¹H NMR (300 MHz, CD₃OD) δ 7.33 (d, J = 1.7 Hz, 1H), 6.95 (s, 1H), 5.07-4.93 (m, 1H), 4.49 (dd, J = 28.4, 13.4 Hz, 1H), 4.02 (dd, J = 25.5, 13.8 Hz, 1H), 3.73-3.54 (m, 2H), 3.42-3.34 (m, 3H), 3.20-2.98 (m, 1H), 2.75-2.55 (m, 1H), 2.46-2.25 (m, 1H), 2.22-1.84 (m, 6H), 1.55-1.09 (m, 3H)； ¹⁹F NMR (282 MHz, CD₃OD) δ -77.05。

Example 156 Compound 111 (4, 5-dichloro-2- ([1- [ (3)R) -pyrrolidine-3-carbonyl]Piperidin-4-yl]Methyl) phenol trifluoroacetic acid)

Step a:

stirring under nitrogen atmosphere at room temperatureR) -3- [4- (4, 5-dichloro-2-hydroxybenzoyl) piperidine-1-carbonyl]To a solution of pyrrolidine-1-carboxylic acid tert-butyl ester (0.35 g, 0.74 mmol) in MeOH (3 mL) was added NaBH₄(56 mg, 1.48 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using PE/EA: (1/2) was eluted, and (3) was obtained as a pale yellow oilR) -3- [4- [ (4, 5-dichloro-2-hydroxyphenyl) (hydroxy) methyl]Piperidine-1-carbonyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (0.20 g, 57%): C₂₂H₃₀Cl₂N₂O₅ [M + H]⁺Calculated lcms (esi): 473, 475 (3: 2), found 473, 475 (3: 2).¹H NMR (400 MHz, CDCl₃) δ 7.03 (d, J =11.3 Hz, 2H), 4.73-4.49 (m, 2H), 4.04-3.82 (m, 1H), 3.73-3.61 (m, 1H), 3.59-3.47 (m, 3H), 3.47-3.29 (m, 2H), 3.27-2.94 (m, 2H), 2.68-2.16 (m, 2H), 1.53-1.42 (m, 3H)。

Step b:

stirring under nitrogen atmosphere at room temperatureR) -3- [4- [ (4, 5-dichloro-2-hydroxyphenyl) (hydroxy) methyl ]Piperidine-1-carbonyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (0.17 g, 0.36 mmol) and Et₃SiH (0.25 g, 2.15 mmol) in DCM (1 mL, 15.73 mmol) was added BF₃.Et₂O (0.41 g, 2.86 mmol). The resulting mixture was stirred at 50 ℃ for 8 hours under nitrogen atmosphere. After cooling to room temperature, the reaction was quenched with water (10 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 20% B to 35% B in 6 minutes; a detector: UV 210 nm; retention time: 4.7 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure, and yielded compound 111 (4, 5-dichloro-2- ([1- [ (3) as an off-white solidR) -pyrrolidine-3-carbonyl]Piperidin-4-yl radical]Methyl) phenol trifluoroacetic acid) (10 mg, 8%): C₁₇H₂₂Cl₂N₂O₂[M + H]⁺Calculated lcms (esi): 357, 359 (3: 2), found 357, 359 (3: 2).¹H NMR (400 MHz, CD₃OD) δ 7.18 (d, J = 2.0 Hz, 1H), 6.91 (s, 1H), 4.61-4.44 (m, 1H), 4.00 (d, J = 13.7 Hz, 1H), 3.74-3.57 (m, 2H), 3.43-3.35 (m, 3H), 3.18-3.06 (m, 1H), 2.73-2.58 (m, 1H), 2.59-2.47 (m, 2H), 2.43-2.30 (m, 1H), 2.15-2.00 (m, 1H), 1.99-1.85 (m, 1H), 1.81-1.65 (m, 2H), 1.36-1.07 (m, 2H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -76.96。

Example 157 Compound 114 (2- [ (2))R) -amino [1- (3-fluoroazetidin-3-carbonyl) piperidin-4-yl]Methyl radical]-4, 5-dichlorophenol)

Step a:

to a stirred 1- [ (tert-butoxy) carbonyl group at room temperature ]To a mixture of-3-fluoroazetidine-3-carboxylic acid (0.21 g, 0.95 mmol) in DMF (2 mL) was added CDI (0.15 g, 0.95 mmol). After stirring for 30 minutes, the resulting solution was added at room temperatureN-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.20 g, 0.48 mmol). The reaction was then stirred at room temperature for an additional 2 hours. The resulting solution was diluted with water (30 mL) and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE/EA (2/1) to give 3- [4- [ (2/1) as a pale yellow solidR) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]Piperidine-1-carbonyl]-3-Fluoroazetidine-1-carboxylic acid tert-butyl ester (0.11 g, 25%): C₂₈H₄₀Cl₂FN₃O₅S [M + H]⁺Calculated lcms (esi): 620, 622 (3: 2), found 620, 622 (3: 2).

Step b:

stirring 3- [4- [ (C) at room temperature under nitrogen atmosphereR) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]Piperidine-1-carbonyl]-3-Fluoroazetidine-1-carboxylate (0.11 g, 0.17 mmol) and Pd (PPh) ₃)₄ (4.0 mg, 0.003 mmol) in THF (2 mL) NaBH was added₄(13 mg, 0.35 mmol). After stirring at room temperature for 1 hour under nitrogen atmosphere, the resulting mixture was quenched with water (30 mL) and extracted with EA (3X 30 mL). Will mergeThe organic layer was washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄Dried and filtered. Concentrating the filtrate under reduced pressure to obtain 3- [4- [ (R) ((R))R) - (4, 5-dichloro-2-hydroxyphenyl) [ (2-methylpropane-2-sulfinyl) amino]Methyl radical]Piperidine-1-carbonyl]3-Fluoroazetidine-1-carboxylic acid tert-butyl ester (0.12 g, crude), which is used directly in the subsequent step without further purification C₂₅H₃₆Cl₂FN₃O₅S[M + H]⁺Calculated lcms (esi): 580, 582 (3: 2), found 580, 582 (3: 2).

Step c:

stirring 3- [4- [ (ii) at room temperatureR) - (4, 5-dichloro-2-hydroxyphenyl) [ (2-methylpropane-2-sulfinyl) amino]Methyl radical]Piperidine-1-carbonyl](iv) -3-Fluoroazetidine-1-carboxylic acid tert-butyl ester (98 mg, 0.17 mmol) in 1, 4-dioxane (5 mL) was added aqueous HCl (6)N3 mL). The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was dissolved in DCM (6 mL), and TFA (3 mL) was added at room temperature. The reaction solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: x Bridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase A: having a NH concentration of 20 mmol/L ₄HCO₃Water, mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 30% B to 80% B in 9 minutes; a detector: UV 254/220 nm; retention time: 7.74 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure to give compound 114 (2- [ (2-)) as an off-white solidR) -amino [1- (3-fluoroazetidin-3-carbonyl) piperidin-4-yl]Methyl radical]-4, 5-dichlorophenol) (35 mg, 54% two-step sum): C₁₆H₂₀Cl₂FN₃O₂ [M + H]⁺Calculated lcms (esi): 376, 378 (3: 2), measured 376, 378 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 6.80 (s, 1H), 4.51 (d, J = 35.4, 9.8 Hz, 1H), 4.30-4.00 (m, 2H), 3.98-3.60 (m, 4H), 3.13-2.90 (m, 1H), 2.80-256 (m, 1H), 2.14-1.95 (m, 2H), 1.55-1.22 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -148.94。

example 158 Compound 119 (, (R)-1-(4-((R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) -2, 3-dihydroxypropan-1-one); compound 120 (, (S)-1-(4-((R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) -2, 3-dihydroxypropan-1-one

Step a:

separation of 1- (4- ((4) by chiral preparative HPLC under the following conditionsR) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) -2, 3-dihydroxypropan-1-one (compound 117, example 145) (35 mg): column: CHIRALPAK IG, 2X 25 cm, 5 μm; mobile phase A: having a NH concentration of 10 mmol/L₃MTBE/MeOH, mobile phase B: MeOH; flow rate: 20 mL/min; gradient: from 10% B to 10% B in 14 minutes; a detector: UV 220/254 nm; retention time: RT (reverse transcription)₁7.47 minutes; RT (reverse transcription) ₂10.05 minutes.

The faster eluting enantiomer was obtained as compound 120 (, (r) as an off-white solid at 7.47 minS)-1-(4-((R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) -2, 3-dihydroxypropan-1-one) (10.2 mg, 29%)₁₅H₂₀Cl₂N₂O₄ [M + H]⁺Lcms (esi) calculated value of (a): 363, 365 (3: 2), measured 363, 365 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 6.87 (s, 1H), 4.68-4.47 (m, 2H), 4.11 ((dd, J = 40.3, 13.8 Hz, 1H), 3.94-3.86 (m, 1H), 3.76-3.53 (m, 2H), 3.20-2.94 (m, 1H), 2.74-2.55 (m, 1H), 2.16-1.92 (m, 2H), 1.57-1.43 (m, 1H), 1.41-1.13 (m, 2H)。

the slower eluting enantiomer was obtained as compound 119 (, (r) as an off-white solid over 10.05 minR)-1-(4-((R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) -2, 3-dihydroxypropan-1-one) (10.1 mg, 29%)₁₅H₂₀Cl₂N₂O₄ [M + H]⁺Calculated lcms (esi): 363, 365 (3: 2), measured 363, 365 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 6.87 (s, 1H), 4.68-4.47 (m, 2H), 4.11 ((dd, J = 40.3, 13.8 Hz, 1H), 3.94-3.86 (m, 1H), 3.76-3.53 (m, 2H), 3.20-2.94 (m, 1H), 2.74-2.55 (m, 1H), 2.16-1.92 (m, 2H), 1.57-1.43 (m, 1H), 1.41-1.13 (m, 2H)。

example 159 Compound 122 (3, 4-dichloro-2- ([1- [ (3-dichloro-2-))R) -pyrrolidine-3-carbonyl]Piperidin-4-yl radical]Methyl) phenol trifluoroacetic acid)

Step a:

to (2, 3-dichloro-6-methoxyphenyl) (piperidin-4-yl) methanol (the free base of intermediate 44, example 44) (0.30 g, 1.03 mmol) and Et at room temperature under a nitrogen atmosphere₃A solution of SiH (2.49 g, 21.54 mmol) in DCM (3 mL) was added BF dropwise₃.Et₂O (1.47 g, 10.34 mmol). The reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was quenched with water (10 mL) and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography, eluting with 45% aqueous ACN (plus 0.05% TFA) to give 4- [ (2, 3-dichloro-6-methoxyphenyl) methyl as an off-white foam ]Piperidine trifluoroacetic acid (0.22 g, 57%): C₁₃H₁₇Cl₂NO [M + H]⁺Lcms (esi) calculated value of (a): 274, 276 (3: 2), found 274, 276 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.40 (d, J = 8.9 Hz, 1H), 6.97 (d, J = 8.9 Hz, 1H), 3.87 (s, 3H), 3.42-3.35 (m, 2H), 3.01-2.84 (m, 4H), 2.13-1.91 (m, 1H), 1.90-1.77 (m, 2H), 1.65-1.50 (m, 2H)。

step b:

at room temperature to (3)R) -1- [ (tert-butoxy) carbonyl]To a solution of pyrrolidine-3-carboxylic acid (0.35 g, 1.60 mmol) in DMF (5 mL) was added CDI (0.26 g, 1.60 mmol). The mixture was stirred at room temperature for 0.5 hour. Et was then added at room temperature₃N (0.73 g, 7.19 mmol) and 4- [ (2, 3-dichloro-6-methoxyphenyl) methyl]Piperidine trifluoroacetic acid (0.220 g, 0.80 mmol). The reaction mixture was stirred at room temperature for an additional 1 hour. The reaction was quenched with water (50 mL) and extracted with EA (3X 10 mL). The combined organic layers were washed with brine (3X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EA (3/2) to give (3) as an off-white foamR) -3- [4- [ (2, 3-dichloro-6-methoxyphenyl) methyl]Piperidine-1-carbonyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (0.20 g, 72%) C₂₃H₃₂Cl₂N₂O₄ [M + H]⁺Calculated lcms (esi): 471, 473 (3: 2), measured values 471, 473 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.31 (d, J = 8.9 Hz, 1H), 6.75 (d, J = 8.9 Hz, 1H), 4.59 (s, 1H), 3.83 (s, 1H), 3.80 (s, 3H), 3.72-3.42 (m, 3H), 3.35 (q, J = 8.7 Hz, 1H), 3.26-3.13 (m, 1H), 3.11-2.91 (m, 1H), 2.81 (d, J = 7.2 Hz, 2H), 2.56 (s, 1H), 2.22 (s, 1H), 2.10-1.82 (m, 2H), 1.67 (s, 1H), 1.48 (s, 9H), 1.37-1.22 (m, 3H)。

step c:

at room temperature to (3)R) -3- [4- [ (2, 3-dichloro-6-methoxyphenyl) (hydroxy) methyl]Piperidine-1-carbonyl]To a solution of pyrrolidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.41 mmol) in DCM (5 mL) was added BBr ₃(1.57 g, 6.35 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was quenched with water (5 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column, 19 mm × 250 mm, 5 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 30% B to 40% B in 6 minutes; a detector: UV 210 nm; retention time: 5.11 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure, and yielded compound 122(3, 4-dichloro-2- ([1- [ (3) as an off-white solidR) -pyrrolidine-3-carbonyl]Piperidin-4-yl radical]Methyl) phenol trifluoroacetic acid) (109.8 mg, 57%): C₁₇H₂₂Cl₂N₂O₂ [M + H]⁺Calculated lcms (esi): 357, 359 (3: 2), found 357, 359 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.20 (d, J =8.7 Hz, 1H), 6.74 (d, J = 8.7 Hz, 1H), 4.55-4.41 (m, 1H), 4.00 (d, J = 13.6 Hz, 1H), 3.71-3.58 (m, 2H), 3.45-3.34 (m, 3H), 3.16-3.04 (m, 1H), 2.82 (d, J = 7.2 Hz, 2H), 2.66 (t, J = 12.6 Hz, 1H), 2.46-2.27 (m, 1H), 2.16-1.96 (m, 2H), 1.83-1.64 (m, 2H), 1.45-1.21 (m, 2H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.04.

example 160. Compound 123 (3, 4-dichloro-2- [ (S))R) -hydroxy ([1- [ (3)R) -pyrrolidine-3-carbonyl]Piperidin-4-yl radical]) Methyl radical]Phenol trifluoroacetic acid); compound 321 (3, 4-dichloro-2- [ (()S) -hydroxy ([1- [ (3)R) -pyrrolidine-3-carbonyl]Piperidin-4-yl radical]) Methyl radical]Phenol trifluoroacetic acid)

Step a:

isolation of 3, 4-dichloro-2- [ hydroxy ([1- [ (3) 3 ] by preparative chiral HPLC under the following conditionsR) -pyrrolidine-3-carbonyl]Piperidin-4-yl radical]) Methyl radical]Phenol trifluoroacetic acid (147.5 mg, 0.40 mmol) column: chiralpak IA, 2X 25 cm, 5 μm; mobile phase A: hexane (plus 0.1% TFA), mobile phase B: EtOH; flow rate: 20 mL/min; gradient: from 20% B to 20% B in 20 minutes; a detector: UV 220 nm; retention time: RT (reverse transcription) ₁6.39 minutes; RT (reverse transcription)₂13.31 minutes.

The faster eluting enantiomer was obtained as compound 123 (3, 4-dichloro-2- [ ()) as a pale pink solid at 6.39 minutesR) -hydroxy ([1- [ (3)R) -pyrrolidine-3-carbonyl]Piperidin-4-yl radical]) Methyl radical]Phenol trifluoroacetic acid) (52 mg, 33%): C₁₇H₂₂Cl₂N₂O₃ [M + H]⁺Calculated lcms (esi): 373, 375 (3: 2), found 373, 375 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.31 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 5.11 (dd, J = 6.8, 3.3 Hz, 1H), 4.58 (t, J = 15.6 Hz, 1H), 4.07 (dd, J = 24.8, 13.9 Hz, 1H), 3.75-3.58 (m, 2H), 3.46-3.34 (m, 3H), 3.15-3.04 (m, 1H), 2.70-2.54 (m, 1H), 2.44-2.27 (m, 1H), 2.27-2.16 (m, 1H), 2.16-1.93 (m, 2H), 1.59-1.26 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.35。

the slower eluting enantiomer was obtained as compound 321 (3, 4-dichloro-2- [ (3, 4-dichloro-2- [)) in the form of a pale pink solid at 13.31 minutesS) -hydroxy ([1- [ (3)R) -pyrrolidine-3-carbonyl]Piperidin-4-yl radical]) Methyl radical]Phenol trifluoroacetic acid) (59 mg, 38%): C₁₇H₂₂Cl₂N₂O₃ [M + H]⁺Calculated lcms (esi): 373, 375 (3: 2), found 373, 375 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.31 (d, J = 8.8 Hz, 1H), 6.77 (dd, J =8.8, 2.9 Hz, 1H), 5.12 (dd, J = 6.6, 2.0 Hz, 1H), 4.58 (dd, J = 22.9, 13.3 Hz, 1H), 4.14-3.96 (m, 1H), 3.73-3.57 (m, 2H), 3.45-3.34 (m, 3H), 3.20-3.03 (m, 1H), 2.71-2.53 (m, 1H), 2.45-2.27 (m, 1H), 2.27-2.15 (m, 1H), 2.15-1.91 (m, 2H), 1.59-1.24 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.21。

example 161 compound 124 (4, 5-dichloro-2- (hydroxy (1- (pyrrolidin-3-ylsulfonyl) piperidin-4-yl) methyl) phenol isomer 1); compound 125 (4, 5-dichloro-2- (hydroxy (1- (pyrrolidin-3-ylsulfonyl) piperidin-4-yl) methyl) phenol isomer 2); compound 121 (4, 5-dichloro-2- (hydroxy (1- (pyrrolidin-3-ylsulfonyl) piperidin-4-yl) methyl) phenol isomer 3); compound 127 (4, 5-dichloro-2- (hydroxy (1- (pyrrolidin-3-ylsulfonyl) piperidin-4-yl) methyl) phenol isomer 4)

Step a:

To stirred Et at room temperature under nitrogen atmosphere₃To a solution of N (0.35 g, 3.47 mmol) and 4- (4, 5-dichloro-2-methoxybenzoyl) piperidine (0.50 g, 1.74 mmol) in DCM (5 mL) was added tert-butyl 3- (chlorosulfonyl) pyrrolidine-1-carboxylate (0.70 g, 2.60 mmol). Stirring at room temperature for 30 minutes under nitrogen atmosphereAfter this time, the resulting mixture was quenched with water (50 mL) and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. Filtering, and concentrating the filtrate under reduced pressure. The residue was purified by preparative TLC eluting with PE/EA (2/1) to give 3- [ [4- (4, 5-dichloro-2-methoxybenzoyl) piperidin-1-yl ] as a pale yellow oil]Sulfonyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (0.65 g, 72%): C₂₂H₃₀Cl₂N₂O₆S [M + H]⁺Calculated lcms (esi): 521, 523 (3: 2), found 521, 523 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.68 (s, 1H), 7.36 (s, 1H), 3.97 (s, 3H), 3.97-3.89 (m, 1H), 3.82 (d, J = 12.5 Hz, 2H), 3.66 (d, J = 6.8 Hz, 2H), 3.60-3.54 (m, 1H), 3.50-3.39 (m, 2H), 3.05 (m, J = 12.0 Hz, 2H), 2.37-2.24 (m, 2H), 1.97 (d, J = 13.3 Hz, 2H), 1.72-1.60 (m, 2H), 1.484 (s, 9H)。

step b:

to a stirred solution of 3- [ [4- (4, 5-dichloro-2-methoxybenzoyl) piperidin-1-yl group at room temperature under a nitrogen atmosphere]Sulfonyl radical]To a solution of pyrrolidine-1-carboxylic acid tert-butyl ester (0.65 g, 1.25 mmol) in DCM (4 mL) was added BBr₃(2.50 g, 9.97 mmol). After stirring at room temperature for 1 hour under a nitrogen atmosphere, the resulting mixture was quenched with water (5 mL) at room temperature. A precipitated solid formed and was collected by filtration. The filter cake was washed with water (3X 5 mL) and dried in a vacuum oven to give 4, 5-dichloro-2- [1- (pyrrolidine-3-sulfonyl) piperidine-4-carbonyl as an off-white solid ]Phenol (0.45 g, 88%) C₁₆H₂₀Cl₂N₂O₄S [M + H]⁺Lcms (esi) calculated value of (a): 407, 409 (3: 2), found 407, 409 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 8.10 (s, 1H), 7.18 (s, 1H), 4.21-4.10 (m, 1H), 3.90 (d, J = 12.5 Hz, 2H), 3.74-3.66 (m, 3H), 3.58-3.40 (m, 2H), 3.19 (t, J = 13.0 Hz, 2H), 2.52-2.42 (m, 2H), 2.00 (d, J = 13.5 Hz, 2H), 1.86-1.71 (m, 2H)。

step c:

stirring at room temperature under nitrogen atmosphere4, 5-dichloro-2- [1- (pyrrolidine-3-sulfonyl) piperidine-4-carbonyl]To a solution of phenol (0.45 g, 1.10 mmol) in MeOH (10 mL) was added NaBH₄(63 mg, 1.66 mmol). After stirring at room temperature for an additional 1 hour, the resulting mixture was quenched with water (2 mL) at room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column 30X 150 mm, 5 μm; mobile phase A: having a NH concentration of 10 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 27% B to 38% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.92 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give 4, 5-dichloro-2- (hydroxy (1- (pyrrolidin-3-ylsulfonyl) piperidin-4-yl) methyl) phenol (0.40 g, 88%) as an off-white solid C₁₆H₂₂Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 409, 411 (3: 2), found 409, 411 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.39 (s, 1H), 6.91 (s, 1H), 4.77 (d, J = 6.2 Hz, 1H), 3.89-3.68 (m, 3H), 3.21-3.12 (m, 2H), 3.09-3.02 (m, 1H), 2.96-2.77 (m, 3H), 2.20-2.00 (m, 2H), 1.92-1.78 (m, 2H), 1.59-1.39 (m, 3H)。

step d:

4, 5-dichloro-2- (hydroxy (1- (pyrrolidin-3-ylsulfonyl) piperidin-4-yl) methyl) phenol (0.40 g, 0.98 mmol) was isolated by chiral preparative HPLC under the following conditions: CHIRALPAK AD-H, 2.0 cm × 25 cm; mobile phase A: hexane (0.1% DEA), mobile phase B: EtOH; flow rate: 18 mL/min; gradient: from 50% B to 50% B in 19 minutes; a detector: UV 220/254 nm; retention time: RT (reverse transcription) ₁7.42 minutes; RT (reverse transcription)₂10.38 minutes; RT (reverse transcription)₃13.56 minutes; RT (reverse transcription)₄15.99 minutes.

The 1 st enantiomer was obtained as compound 124 (4, 5-dichloro-2- (hydroxy (1- (pyrrolidin-3-ylsulfonyl) piperidin-4-yl) methyl) phenol isomer 1) (30.4 mg, 8%) as an off-white solid at 7.42 minutes: C₁₆H₂₂Cl₂N₂O₄S [M + H]⁺Lcms (esi) calculated value of (a): 409, 411 (3: 2), found value 409, 411 (3 : 2)； ¹H NMR (400 MHz, CD₃OD) δ 7.39 (s, 1H), 6.91 (s, 1H), 4.77 (d, J = 6.2 Hz, 1H), 3.89-3.68 (m, 3H), 3.21-3.12 (m, 2H), 3.09-3.02 (m, 1H), 2.96-2.77 (m, 3H), 2.20-2.00 (m, 2H), 1.92-1.78 (m, 2H), 1.59-1.39 (m, 3H)。

The 2 nd enantiomer was obtained as compound 125 (4, 5-dichloro-2- (hydroxy (1- (pyrrolidin-3-ylsulfonyl) piperidin-4-yl) methyl) phenol isomer 2) (29.8 mg, 7%) C as an off-white solid at 10.38 minutes₁₆H₂₂Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 409, 411 (3: 2), found 409, 411 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.39 (s, 1H), 6.91 (s, 1H), 4.77 (d, J = 6.2 Hz, 1H), 3.89-3.68 (m, 3H), 3.21-3.12 (m, 2H), 3.09-3.02 (m, 1H), 2.96-2.77 (m, 3H), 2.20-2.00 (m, 2H), 1.92-1.78 (m, 2H), 1.59-1.39 (m, 3H)。

the 3 rd enantiomer was obtained as compound 121 (4, 5-dichloro-2- (hydroxy (1- (pyrrolidin-3-ylsulfonyl) piperidin-4-yl) methyl) phenol isomer 3) (29.3 mg, 7%) as an off-white solid at 13.56 minutes: C%₁₆H₂₂Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 409, 411 (3: 2), found 409, 411 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.39 (s, 1H), 6.91 (s, 1H), 4.77 (d, J = 6.2 Hz, 1H), 3.89-3.68 (m, 3H), 3.21-3.12 (m, 2H), 3.09-3.02 (m, 1H), 2.96-2.77 (m, 3H), 2.20-2.00 (m, 2H), 1.92-1.78 (m, 2H), 1.59-1.39 (m, 3H)。

the 4 th enantiomer was obtained as compound 127 (4, 5-dichloro-2- (hydroxy (1- (pyrrolidin-3-ylsulfonyl) piperidin-4-yl) methyl) phenol isomer 4) (27.5 mg, 7%) C as an off-white solid at 15.99 min% ₁₆H₂₂Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 409, 411 (3: 2), found 409, 411 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.39 (s, 1H), 6.91 (s, 1H), 4.77 (d, J = 6.2 Hz, 1H), 3.89-3.68 (m, 3H), 3.21-3.12 (m, 2H), 3.09-3.02 (m, 1H), 2.96-2.77 (m, 3H), 2.20-2.00 (m, 2H), 1.92-1.78 (m, 2H), 1.59-1.39 (m, 3H)。

EXAMPLE 162 Compound 126 (3, 4-dichloro-2- [ hydroxy ([1- [ (3)R) -pyrrolidine-3-carbonyl]Piperidin-4-yl radical]) Methyl radical]Phenol trifluoroacetic acid)

Step a:

at room temperature to (3)R) -1- [ (tert-butoxy) carbonyl]To a solution of pyrrolidine-3-carboxylic acid (0.40 g, 1.86 mmol) in DMF (8 mL) was added CDI (0.34 mg, 2.07 mmol). After stirring at room temperature for 0.5 h, Et was added at room temperature₃N (0.11 g, 10.79 mmol) and (2, 3-dichloro-6-methoxyphenyl) (piperidin-4-yl) methanol (0.30 g, 1.03 mmol) were added to the resulting solution. After stirring at room temperature for an additional 1 hour, the resulting mixture was quenched with water (80 mL) and extracted with EA (3X 25 mL). The organic phases were combined, washed with brine (4X 10 mL), over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography, eluting with EA to give (3) as an off-white foamR) -3- [4- [ (2, 3-dichloro-6-methoxyphenyl) (hydroxy) methyl]Piperidine-1-carbonyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (0.20 g, 50%): C₂₃H₃₂Cl₂N₂O₅ [M + H-56]⁺Calculated lcms (esi): 431, 433 (3: 2), found 431, 433 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.38 (d, J = 8.9 Hz, 1H), 6.83 (d, J =9.0 Hz, 1H), 4.99 (d, J = 8.5 Hz, 1H), 4.65 (dd, J = 57.9, 13.0 Hz, 1H), 3.92 (s, 4H), 3.73-2.87 (m, 7H), 2.52 (dt, J = 38.5, 12.3 Hz, 1H), 2.3-1.8 (m, 4H), 1.47 (s, 9H), 1.41-1.29 (m, 3H)。

step b:

at room temperature to (3)R) -3- [4- [ (2, 3-dichloro-6-methoxyphenyl) (hydroxy) methyl ]Piperidine-1-carbonyl]To a solution of pyrrolidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.41 mmol) in DCM (5 mL) was added BBr₃(1.56 g, 6.35 mmol). Will be provided withThe reaction mixture was stirred at room temperature for 3 hours. The reaction was then quenched with water (5 mL) at 0 ℃. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 19 mm x 250 mm, 10 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 25% B to 33% B in 6 minutes; a detector: UV 210 nm; retention time 4.15 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure, and the compound 126 (3, 4-dichloro-2- [ hydroxy ([1- [ (3) was obtained as an off-white solidR) -pyrrolidine-3-carbonyl]Piperidin-4-yl radical]) Methyl radical]Phenol trifluoroacetic acid) (147.5 mg, 76%): C₁₇H₂₂Cl₂N₂O₃ [M + H]⁺Calculated lcms (esi): 373, 375 (3: 2), found 373, 375 (3: 2).¹H NMR (400 MHz, DMSO-d ₆) δ 10.19 (s, 1H), 8.93 (d, J = 29.9 Hz, 2H), 7.37 (d, J = 8.8 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H), 6.50 (br, 1H), 4.94 (d, J =7.2 Hz, 1H), 4.42 (dd, J = 27.3, 13.0 Hz, 1H), 3.95 (dd, J = 27.8, 13.6 Hz, 1H), 3.61-3.45 (m, 1H), 3.33-3.07 (m, 3H), 3.06-2.86 (m, 1H), 2.50-2.40 (m, 2H), 2.29-2.09 (m, 2H), 2.02-1.78 (m, 2H), 1.49-0.97 (m, 3H)； ¹⁹F NMR (376 MHz, DMSO-d ₆) δ -74.32。

EXAMPLE 163 Compound 128 (4, 5-dichloro-2- [ hydroxy ([1- [ (3) hydroxy)S) -pyrrolidine-3-carbonyl]Azepan-4-yl]) Methyl radical]Phenol)

Step a:

to a stirred solution of 1, 2-dichloro-3-iodo-4- (prop-2-en-1-yloxy) benzene (0.60 g, 1.82 mmol) in THF (10 mL) at 0 deg.C under an argon atmosphere was added dropwise iPrMgCl (1.37 mL, 2.74 mmol, 2M in THF). The resulting solution was stirred at 0 ℃ for 0.5 hour under an argon atmosphere. 4-formylazepane-1-carboxylic acid tert-butyl ester (0.50 g, 2.19 mmol) was then reacted at 0 ℃ under an argon atmosphereA solution in THF (1 mL) was added dropwise to the resulting solution. The resulting solution was stirred at room temperature for an additional 1 hour. The reaction was quenched with saturated NH at room temperature₄Aqueous Cl (20 mL) was quenched. The resulting mixture was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE/EA (1/1) to give 4- [ [2, 3-dichloro-6- (prop-2-en-1-yloxy) phenyl ] in the form of a pale yellow oil](hydroxy) methyl group]N-heptane-1-carboxylic acid tert-butyl ester (0.65 g, 75%): C₂₁H₂₉Cl₂NO₄ [M + H]⁺Calculated lcms (esi): 430, 432 (3: 2), found 430, 432 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.34 (d, J = 8.9 Hz, 1H), 6.80 (d, J = 8.9 Hz, 1H), 6.10-5.92 (m, 1H), 5.47-5.33 (m, 2H), 4.95 (t, J = 8.9 Hz, 1H), 4.69-4.57 (m, 2H), 3.69-3.36 (m, 2H), 3.36-3.11 (m, 2H), 2.39 (d, J = 14.3 Hz, 1H), 2.07 (s, 1H), 1.85-1.71 (m, 1H), 1.66-1.49 (m, 1H), 1.49-1.42 (m, 10H), 1.43-1.22 (m, 2H)。

step b:

to a stirred 4- [ [2, 3-dichloro-6- (prop-2-en-1-yloxy) phenyl group at room temperature](hydroxy) methyl group]To a solution of azepane-1-carboxylic acid tert-butyl ester (0.65 g, 1.51 mmol) in DCM (8 mL) was added TFA (4 mL). The resulting solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure to give (azepan-4-yl) [2, 3-dichloro-6- (prop-2-en-1-yloxy) phenyl ] in the form of a yellow oil ]Methanol (0.60 g, crude), which was used in the next step without further purification: c₁₆H₂₁Cl₂NO₂ [M + H]⁺Lcms (esi) calculated value of (a): 330, 332 (3: 2), found 330, 332 (3: 2);

step c:

stirring at room temperature (3)S) -1- [ (tert-butoxy) carbonyl]To a solution of pyrrolidine-3-carboxylic acid (0.52 g, 2.42 mmol) and HATU (0.92 g, 2.42 mmol) in DMF (5 mL) was added (azepan-4-yl) [2, 3-dichloro-6- (prop-2-en-1-yloxy) phenyl]Methanol (0.40 g, 1.21 mmol) and Et₃N (0.24 g, 2.42 mmol). The resulting solution was stirred at room temperature for 2 hours. The reaction was diluted with water (20 mL) at room temperature. The resulting mixture was extracted with EA (3X 50 mL). The combined organic layers were washed with brine (6X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (5/1) to give (3) as an off-white semisolidS) -3- (4- [ [2, 3-dichloro-6- (prop-2-en-1-yloxy) phenyl)](hydroxy) methyl group]Azepane-1-carbonyl) pyrrolidine-1-carboxylic acid tert-butyl ester (0.48 g, 60% of two stages in total) C₂₆H₃₆Cl₂N₂O₅ [M + H]⁺Calculated lcms (esi): 527, 529 (3: 2), found 527, 529 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.39-7.32 (m, 1H), 6.89-6.71 (m, 1H), 6.09-5.96 (m, 1H), 5.48-5.33 (m, 2H), 4.99-4.90 (m, 1H), 4.68-4.59 (m, 2H), 3.88-3.52 (m, 4H), 3.52-3.27 (m, 4H), 3.27-3.04 (m, 1H), 2.58-2.35 (m, 1H), 2.30-1.96 (m, 3H), 1.88 (dd, J = 31.0, 12.6 Hz, 1H), 1.68-1.53 (m, 1H), 1.53-1.43 (m, 10H), 1.43-1.22 (m, 2H)。

step d:

stirring under nitrogen atmosphere at room temperature S) -3- (4- [ [2, 3-dichloro-6- (prop-2-en-1-yloxy) phenyl)](hydroxy) methyl group]Azepane-1-carbonyl) pyrrolidine-1-carboxylic acid tert-butyl ester (0.48 g, 0.91 mmol) and Pd (PPh)₃)₄(21 mg, 0.02 mmol) in THF (5 mL) NaBH was added₄(69 mg, 1.82 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated NH at 0 deg.C₄Aqueous Cl (10 mL) was quenched. The resulting mixture was extracted with EA (3X 20 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 40% aqueous ACN (plus 0.05% TFA) to give (3) as an off-white solidS) -3- [4- [ (2, 3-dichloro-6-hydroxyphenyl) (hydroxy) methyl]Azepane-1-carbonyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (0.40 g, 90%): C₂₃H₃₂Cl₂N₂O₅ [M + H]⁺Calculated lcms (esi): 487, 489 (3: 2), found 487, 489 (3: 2);

step e:

stirring at room temperature (3)S) -3- [4- [ (4, 5-dichloro-2-hydroxyphenyl) (hydroxy) methyl]Azepane-1-carbonyl]To a solution of pyrrolidine-1-carboxylic acid tert-butyl ester (10 mg, 0.06 mmol) in DCM (3 mL) was added TFA (1.5 mL). The resulting solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xselect CSH OBD column 30 × 150 mm 5 μm n; mobile phase A: has 10 mmoL/L NH ₄HCO₃Water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 5% B to 40% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.62 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 128 (4, 5-dichloro-2- [ hydroxy ([1- [ (3) as an off-white solidS) -pyrrolidine-3-carbonyl]Azepan-4-yl]) Methyl radical]Phenol) (2.7 mg, 36% two-step sum): C₁₈H₂₄Cl₂N₂O₃ [M + H]⁺Calculated lcms (esi): 387, 389 (3: 2), found 387, 389 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.31-7.19 (m, 1H), 6.75-6.64 (m, 1H), 5.16-5.01 (m, 1H), 3.86-3.63 (m, 2H), 3.63-3.49 (m, 1H), 3.49-3.34 (m, 2H), 3.29-3.10 (m, 3H), 3.12-2.98 (m, 1H), 2.30-1.81 (m, 5H), 1.81-1.35 (m, 4H)。

EXAMPLE 164 Compound 322 (3, 4-dichloro-2- [ (R) -hydroxy [1- [ (3S) -pyrrolidine-3-carbonyl ] azepan-4-yl ] methyl ] phenol trifluoroacetic acid isomer 1); the compound 129 (isomer 2 of 3, 4-dichloro-2- [ (S) -hydroxy [1- [ (3S) -pyrrolidine-3-carbonyl ] azepan-4-yl ] methyl ] phenol trifluoroacetic acid); compound 323 (3, 4-dichloro-2- [ (R) -hydroxy [1- [ (3S) -pyrrolidine-3-carbonyl ] azepan-4-yl ] methyl ] phenol trifluoroacetic acid isomer 3); and the compound 130 (3, 4-dichloro-2- [ (S) -hydroxy [1- [ (3S) -pyrrolidine-3-carbonyl ] azepan-4-yl ] methyl ] phenol trifluoroacetic acid isomer 4)

Step a:

isolation by preparation of SFC under the following conditions (3)S) -3- [4- [ (2, 3-dichloro-6-hydroxyphenyl) (hydroxy) methyl ]Azepane-1-carbonyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (350 mg, 0.72 mmol) column: chiral pak AD-H, 2X 25 cm (5 μm); mobile phase A: CO 2₂ (70%), mobile phase B: IPA (2 mM NH)₃-MeOH); flow rate: 50 mL/min; gradient: 18% of B; a detector: UV 220 nm; retention time: RT (reverse transcription)₁6.75 min, RT₂7.90 minutes, RT₃8.67 min, RT₃8.67 min, RT₄11.57 minutes. Injection volume 0.4 mL.

Peak 1 was collected at 6.75 minutes and concentrated under reduced pressure to give (3) as an off-white solidS)-3-[(4R)-4-[(S) - (2, 3-dichloro-6-hydroxyphenyl) (hydroxy) methyl]Azepane-1-carbonyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (55 mg, 16%).

Peak 2 was collected at 7.90 minutes and concentrated under reduced pressure to give (3) as an off-white solidS)-3-[(4S)-4-[(S) - (2, 3-dichloro-6-hydroxyphenyl) (hydroxy) methyl]Azepane-1-carbonyl]Pyrrolidine-1-carboxylate (35 mg, 10%).

Peak 4 was collected at 11.57 min and concentrated under reduced pressure to give (3) as an off-white solidS)-3-[(4S)-4-[(R) - (2, 3-dichloro-6-hydroxyphenyl) (hydroxy) methyl]Azepane-1-carbonyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (50 mg, 14%).

Peak 3 was collected at 8.67 min and concentrated under reduced pressure. The residue was purified by preparative chiral HPLC on column: CHIRAL ART Cellulose-SB, 2X 25 cm, 5 μm; mobile phase A: hexane (plus 0.1% FA), mobile phase B: EtOH; flow rate: 20 mL/min; gradient: from 10% B to 10% B in 14 minutes; a detector: UV 254/220 nm; retention time: 10.26 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give (3) as an off-white solid S)-3-[(4R)-4-[(R) - (2, 3-dichloro-6-hydroxyphenyl) (hydroxy) methyl]Azepane-1-carbonyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (40 mg, 11%).

Step b:

stirring at room temperature (3)S)-3-[(4R)-4-[(S) - (2, 3-dichloro-6-hydroxyphenyl) (hydroxy) methyl]Azepane-1-carbonyl]To a solution of pyrrolidine-1-carboxylic acid tert-butyl ester (55 mg, 0.113 mmol) in DCM (1 mL) was added TFA (0.5 mL). The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xselect CSH OBD column 30 × 150 mm 5 μm, mobile phase a: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 5% B to 40% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.62 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure, and the compound 322 (3, 4-dichloro-2- [ (R) -hydroxy [ -1- [ (3S) -pyrrolidine-3-carbonyl) was obtained as an off-white solid]Azepan-4-yl]Methyl radical]Phenol trifluoroacetic acid isomer 1) (20 mg, 34%): C₁₈H₂₄Cl₂N₂O₃ [M + H]⁺Calculated lcms (esi): 387, 389 (3: 2), found 387, 389 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.30 (dd, J = 8.8, 4.6 Hz, 1H), 6.76 (dd, J = 8.8, 6.3 Hz, 1H), 5.09 (dd, J = 6.2, 3.2 Hz, 1H), 3.78-3.64 (m, 2H), 3.64-3.47 (m, 3H), 3.47-3.35 (m, 4H), 2.48-2.24 (m, 1H), 2.24-1.90 (m, 4H), 1.78-1.51 (m, 3H), 1.51-1.32 (m, 1H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.11。

stirring at room temperature (3)S)-3-[(4S)-4-[(S) - (2, 3-dichloro-6-hydroxyphenyl) (hydroxy) methyl]Azepane-1-carbonyl ]To a solution of pyrrolidine-1-carboxylic acid tert-butyl ester (35 mg, 0.07 mmol) in DCM (1 mL) was added TFA (0.5 mL). The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Prep C18 OBD column 19X 150 mm 5 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 15% B to 42% B in 7 minutes; a detector: UV 254/220 nm; retention time: 5.47 minutes. Collecting the fractions containing the desired product, concentrating under reduced pressure to obtain the desired product as an off-white solidThe compound 129 (3, 4-dichloro-2- [ (S) -hydroxy [1- [ (3S) -pyrrolidine-3-carbonyl]Azepan-4-yl]Methyl radical]Phenol trifluoroacetic acid isomer 2) (19 mg, 50%): C₁₈H₂₄Cl₂N₂O₃ [M + H]⁺Calculated lcms (esi): 387, 389 (3: 2), found 387, 389 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.30 (dd, J = 8.8, 4.2 Hz, 1H), 6.75 (dd, J = 8.8, 3.1 Hz, 1H), 5.13 (dd, J =11.7, 6.0 Hz, 1H), 3.93-3.72 (m, 1H), 3.72-3.58 (m, 3H), 3.58-3.48 (m, 1H), 3.48-3.34 (m, 4H), 2.44-2.30 (m, 1H), 2.24-1.87 (m, 4H), 1.82-1.43 (m, 4H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.01。

stirring at room temperature (3)S)-3-[(4R)-4-[(R) - (2, 3-dichloro-6-hydroxyphenyl) (hydroxy) methyl]Azepane-1-carbonyl]To a solution of pyrrolidine-1-carboxylic acid tert-butyl ester (40 mg, 0.08 mmol) in DCM (1 mL) was added TFA (0.5 mL). The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column 19X 150 mm, 5 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 2% B to 19% B in 10 minutes; a detector: UV 254/220 nm; retention time: 6.63 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure and provided compound 323 (3, 4-dichloro-2- [ (S) -hydroxy [1- [ (3S) -pyrrolidine-3-carbonyl) as an off-white solid ]Azepan-4-yl]Methyl radical]Phenol trifluoroacetic acid isomer 3) (29 mg, 67%): C₁₈H₂₄Cl₂N₂O₃ [M + H]⁺Lcms (esi) calculated value of (a): 387, 389 (3: 2), found 387, 389 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.30 (dd, J = 8.8, 4.9 Hz, 1H), 6.76 (dd, J = 8.8, 7.2 Hz, 1H), 5.09 (dd, J =10.0, 6.3 Hz, 1H), 3.85-3.73 (m, 2H), 3.73-3.49 (m, 3H), 3.47-3.34 (m, 4H), 2.42-2.29 (m, 1H), 2.21-1.99 (m, 3H), 1.99-1.87 (m, 1H), 1.80-1.36 (m, 4H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.03。

stirring at room temperature (3)S)-3-[(4S)-4-[(R) - (2, 3-dichloro-6-hydroxyphenyl) (hydroxy) methyl]Azepane-1-carbonyl]To a solution of pyrrolidine-1-carboxylic acid tert-butyl ester (50 mg, 0.10 mmol) in DCM (1 mL) was added TFA (0.5 mL). The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xselect CSH OBD column 30X 150 mm 5 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 5% B to 40% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.62 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure, and the compound 130 (3, 4-dichloro-2- [ (S) -hydroxy [1- [ (3S) -pyrrolidine-3-carbonyl) was obtained as an off-white solid]Azepan-4-yl]Methyl radical]Phenol trifluoroacetic acid isomer 4) (43 mg, 79%): C₁₈H₂₄Cl₂N₂O₃ [M + H]⁺Calculated lcms (esi): 387, 389 (3: 2), found 387, 389 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.30 (dd, J = 8.8, 4.3 Hz, 1H), 6.75 (dd, J = 8.8, 3.1 Hz, 1H), 5.16-5.06 (m, 1H), 3.83-3.55 (m, 4H), 3.55-3.34 (m, 5H), 2.46-2.23 (m, 1H), 2.23-1.88 (m, 4H), 1.80-1.45 (m, 4H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.11。

example 165 Compound 132 (2- [ (()R) -amino [1- (2-methoxyethanesulfonyl) piperidin-4-yl group ]Methyl radical]-4, 5-dichlorophenol trifluoroacetic acid)

A, step a:

stirring at 0 ℃: (S)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.10 g, 0.24 mmol) and Et₃To a mixture of N (48 mg, 0.48 mmol) in DCM (1 mL) was added 2-methoxyethane-1-sulfonyl chloride (45 mg, 0.29 mmol). The resulting mixture was stirred at 0 ℃ for 2 hours. The resulting mixture was diluted with water (20 mL) at 0 deg.CFor dilution, extract with EA (3X 20 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC, eluting with PE/EA (5/1), to give (a) as a colorless oilS)-N- [ (R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (2-Methoxyethanesulfonyl) piperidin-4-yl group]Methyl radical]2-methylpropane-2-sulfinamide (90 mg, 56%): C₂₂H₃₄Cl₂N₂O₅S₂ [M + H]⁺Calculated lcms (esi): 541, 543 (3: 2), measured value 541, 543 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.23 (s, 1H), 6.98 (s, 1H), 6.10-5.92 (m, 1H), 5.46-5.31 (m, 2H), 4.61-4.41 (m, 3H), 3.86-3.77 (m, 2H), 3.74 (t, J = 6.0 Hz, 2H), 3.37 (s, 3H), 3.18 (t, J = 6.0 Hz, 2H), 2.78-2.61 (m, 2H), 1.90-1.79 (m, 1H), 1.79-1.59 (m, 1H), 1.54-1.40 (m, 1H), 1.40-1.23 (m, 2H), 1.17 (s, 9H)。

step b:

stirring under nitrogen atmosphere at room temperatureS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (2-Methoxyethanesulfonyl) piperidin-4-yl group]Methyl radical]-2-methylpropane-2-sulfinamide (90 mg, 0.17 mmol) and Pd (PPh) ₃)₄(2 mg, 0.002 mmol) in THF (1 mL) was added NaBH₄(13 mg, 0.34 mmol). After stirring at room temperature for 1 hour, the resulting mixture was taken up with saturated NH₄Aqueous Cl solution (1 mL) was quenched and concentrated under reduced pressure to give (A) as a pale yellow solidS)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) [1- (2-methoxyethanesulfonyl) piperidin-4-yl]Methyl radical]-2-methylpropane-2-sulfinamide (90 mg, crude), which was used in the next step without further purification: c₁₉H₃₀Cl₂N₂O₅S₂ [M + H]⁺Calculated lcms (esi): 501, 503 (3: 2), found 501, 503 (3: 2).

Step c:

will (a) toS)-N- [ (R) - (4, 5-dichloro-2-hydroxyphenyl) [1- (2-methoxyethanesulfonyl) piperidin-4-yl ] amine]Methyl radical]2-methylpropane-2-sulfinamide (90 mg, 0.18 mmol) and HCl (4)N1 mL) solution in 1, 4-dioxane (1 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xselect CSH OBD column 30 × 150 mm, 5 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 10% B to 33% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.63 minutes. Collecting the fractions containing the desired product, concentrating under reduced pressure to obtain compound 132 (2- [ (2-)) as a purple solid R) -amino [1- (2-methoxyethanesulfonyl) piperidin-4-yl]Methyl radical]-4, 5-dichlorophenol trifluoroacetic acid) (47.4 mg, 56% in two steps total) C₁₅H₂₂Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 397, 399 (3: 2), found 397, 399 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.44 (s, 1H), 7.09 (s, 1H), 4.18 (d, J = 9.8 Hz, 1H), 3.84 (d, J = 12.5 Hz, 1H), 3.77-3.65 (m, 3H), 3.36 (s, 3H), 3.28 (t, J = 5.7 Hz, 2H), 2.87 (td, J = 12.3, 2.6 Hz, 1H), 2.76 (td, J =12.2, 2.9 Hz, 1H), 2.28-2.16 (m, 1H), 2.02 (d, J = 12.9 Hz, 1H), 1.55-1.22 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -76.98.

example 166 Compound 110 (2- [ (2- [))R) -amino [1- (pyrrolidine-3-sulfonyl) piperidin-4-yl]Methyl radical]-4, 5-dichlorophenol)

Step a:

stirring at room temperature under argon atmosphereN-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide (50 mg, 0.12 mmol) and Et₃To a solution of N (25 mg, 0.25 mmol) in DCM (2 mL) was added tert-butyl 3- (chlorosulfonyl) pyrrolidine-1-carboxylate (45 mg, 0.17 mmol). The resulting mixture was stirred at room temperature for 4 hours under argon atmosphere. The resulting mixture was concentrated under reduced pressure.The residue was purified by preparative TLC, eluted with PE/EA (1/4) to give 3- ([4- [ ((1/4) as a pale yellow oilR) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]Piperidin-1-yl radical]Sulfonyl) pyrrolidine-1-carboxylic acid tert-butyl ester (25 mg, 32%): C₂₈H₄₃Cl₂N₃O₆S₂ [M + H]⁺Calculated lcms (esi): 652, 654 (3: 2), found 652, 654 (3: 2);¹H NMR (300 MHz, CDCl₃) δ 7.21 (s, 1H), 6.98 (s, 1H), 6.10-5.94 (m, 1H), 5.46-5.29 (m, 2H), 4.59-4.54 (m, 2H), 4.41 (s, 1H), 3.94-3.76 (m, 3H), 3.75-3.53 (m, 4H), 3.37 (dt, J = 10.8, 7.7 Hz, 1H), 2.86-2.67 (m, 2H), 2.17-2.02 (m, 1H), 1.96-1.78 (m, 1H), 1.47 (s, 9H), 1.39-1.20 (m, 4H), 1.15 (s, 9H)。

step b:

to stirred 3- ([4- [ ((C) at room temperature under nitrogen atmosphere R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][ (2-methylpropane-2-sulfinyl) amino group]Methyl radical]Piperidin-1-yl]Sulfonyl) pyrrolidine-1-carboxylic acid tert-butyl ester (0.14 g, 0.22 mmol) and Pd (PPh)₃)₄(24 mg, 0.02 mmol) in THF (3 mL) NaBH was added portionwise₄(26 mg, 0.69 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The resulting mixture was quenched with water (30 mL) at room temperature and extracted with EA (3X 20 mL). The combined organic layers were washed with EA (3X 5 mL) over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC, eluted with PE/EA (1/4) to give 3- ([4- [ ((1/4) as a pale yellow solidR) - (4, 5-dichloro-2-hydroxyphenyl) [ (2-methylpropane-2-sulfinyl) amino]Methyl radical]Piperidin-1-yl radical]Sulfonyl) pyrrolidine-1-carboxylic acid tert-butyl ester (0.10 g, 73%); c₂₅H₃₉Cl₂N₃O₆S₂ [M + H]⁺Calculated lcms (esi): 612, 614 (3: 2), found 612, 614 (3: 2).

Step c:

stirring 3- ([4- [ (4- [)) at room temperatureR) - (4, 5-dichloro-2-hydroxyphenyl) [ (2-methylpropane-2-sulfinyl)Amino group]Methyl radical]Piperidin-1-yl radical]Sulfonyl) pyrrolidine-1-carboxylic acid tert-butyl ester (0.10 g, 0.16 mmol) in 1, 4-dioxane (5 mL) was added aqueous HCl (6 mL) N3 mL). The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was dissolved in DCM (6 mL), and TFA (3 mL) was added at room temperature. The reaction solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 5 μm, 19 mm × 250 mm; mobile phase A: having a NH concentration of 10 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 10% B to 80% B in 6 minutes; a detector: UV 254 nm; retention time: 5.7 minutes. Collecting the fractions containing the desired product, concentrating under reduced pressure to obtain compound 110 (2- [ (2- [)) as an off-white solidR) -amino [1- (pyrrolidine-3-sulfonyl) piperidin-4-yl]Methyl radical]-4, 5-dichlorophenol) (20 mg, 30%). C₁₆H₂₃Cl₂N₃O₃S [M + H]⁺Calculated lcms (esi): 408, 410 (3: 2), found 408, 410 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.23 (s, 1H), 6.87 (s, 1H), 3.98-3.82 (m, 2H), 3.82-3.65 (m, 2H), 3.20-3.11 (m, 2H), 3.02 (dt, J = 13.1, 6.7 Hz, 1H), 2.95-2.71 (m, 3H), 2.20-1.81 (m, 4H), 1.55-1.44 (m, 1H), 1.44-1.20 (m, 2H)。

EXAMPLE 167 Compound 112 (2- [ (R) -amino ([1- [ pyrrolidine-3-sulfonyl ] piperidin-4-yl ] methyl ] -4, 5-dichlorophenol isomer 1); compound 118 (2- [ (R) -amino ([1- [ pyrrolidine-3-sulfonyl ] piperidin-4-yl ] methyl ] -4, 5-dichlorophenol isomer 2)

Step a:

separation of 2- [ (ii) by chiral preparative HPLC under the following conditions R) -amino [1- (pyrrolidine-3-sulfonyl) piperidin-4-yl]Methyl radical]-4, 5-dichlorophenol (20 mg, 0.049 mmol) (compound 110, example 166) column: chiralpak ID-2, 2 × 25 cm, 5 μm; mobile phase A:MeOH (0.1% IPA), mobile phase B: none; flow rate: 16 mL/min; gradient: from 100% a to 100% a in 13 minutes; a detector: UV 220/254 nm; retention time: RT (reverse transcription)₁6.191 minutes; RT (reverse transcription)₂10.888 minutes.

The faster eluting enantiomer was obtained as compound 118 (2- [ (2- [)) as an off-white solid at 6.191 minutesR) -amino ([1- [ pyrrolidine-3-sulfonyl)]Piperidin-4-yl radical]) Methyl radical]-4, 5-dichlorophenol isomer 2) (8.1 mg, 40%): C₁₆H₂₃Cl₂N₃O₃S [M + H]⁺Calculated lcms (esi): 408, 410 (3: 2), found 408, 410 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.23 (s, 1H), 6.87 (s, 1H), 3.91 (d, J =7.7 Hz, 1H), 3.86-3.66 (m, 3H), 3.20-3.11 (m, 2H), 3.09-2.95 (m, 1H), 2.93-2.73 (m, 3H), 2.17-2.02 (m, 2H), 2.05-1.80 (m, 2H), 1.49 (d, J = 13.0 Hz, 1H), 1.41-1.24 (m, 2H)。

the slower eluting enantiomer was obtained as compound 112 (2- [ (2- [)) as an off-white solid at 10.888 minutesR) -amino ([1- [ pyrrolidine-3-sulfonyl)]Piperidin-4-yl radical]) Methyl radical]-4, 5-dichlorophenol isomer 1) (7.7 mg, 38%): C₁₆H₂₃Cl₂N₃O₃S [M + H]⁺Calculated lcms (esi): 408, 410 (3: 2), found 408, 410 (3: 2); ¹H NMR (300 MHz, CD₃OD) δ 7.23 (s, 1H), 6.87 (s, 1H), 3.99-3.85 (m, 2H), 3.81-3.67 (m, 2H), 3.21-3.11 (m, 2H), 3.09-2.95 (m, 1H), 2.94-2.71 (m, 3H), 2.18-2.06 (m, 2H), 2.05-1.79 (m,2H), 1.49 (d, J = 13.3 Hz, 1H), 1.44-1.22 (m, 2H)。

example 168 Compound 141 (2- [ (()R) -amino [1- (piperazine-1-carbonyl) piperidin-4-yl]Methyl radical]-4, 5-dichlorophenol trifluoroacetic acid)

Step a:

Under nitrogen atmosphere, stirring at 0 ℃: (S)-N-[(R)-[4,5-Dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]To a solution of (E) -2-methylpropane-2-sulfinamide (0.10 g, 0.238 mmol) and piperazine-1-carboxylic acid tert-butyl ester (67 mg, 0.358 mmol) in DCM (4 mL) was added bis (trichloromethyl) carbonate (0.10 g, 0.36 mmol) and Et₃N (48 mg, 0.48 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The resulting mixture was quenched with water (30 mL) and extracted with EA (3X 15 mL). The combined organic layers were washed with brine (3X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 75% aqueous ACN (plus 0.05% TFA) to give 4- [4- [ (r) ((r)) as a pale yellow solidR) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidine-1-carbonyl]Piperazine-1-carboxylic acid tert-butyl ester (0.10 g, 66%): C₂₉H₄₄Cl₂N₄O₅S [M + H]⁺Calculated lcms (esi): 631, 633 (3: 2), found 631, 633 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.22 (s, 1H), 6.97 (s, 1H), 6.06-6.01 (m, 1H), 5.49-5.31 (m, 2H), 4.63-4.54 (m, 2H), 4.45-4.31 (m, 1H), 3.73 (dd, J = 25.4, 13.1 Hz, 2H), 3.45-3.40 (m, 4H), 3.22-3.17 (m, 4H), 2.68 (dd, J = 29.0, 16.0 Hz, 2H), 2.08-2.04 (m, 1H), 1.92-1.88 (m, 1H), 1.79-1.68 (m, 1H), 1.48 (s, 9H), 1.38-1.34 (m, 1H), 1.30-1.25 (m, 1H), 1.15 (s, 9H)。

step b:

stirring 4- [4- [ ((s) at room temperature under nitrogen atmosphereR) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical ]Piperidine-1-carbonyl]Piperazine-1-carboxylic acid tert-butyl ester (0.15 g, 0.24 mmol) and Pd (PPh)₃)₄(27 mg, 0.02 mmol) in THF (3 mL) was added NaBH portionwise₄(18 mg, 0.47 mmol). After stirring at room temperature for 1 hour under nitrogen atmosphere, the resulting mixture was quenched with water (2 mL) at room temperature and concentrated under reduced pressure. The crude product was used without further purification in the subsequent step: c₂₆H₄₀Cl₂N₄O₅S [M + H]⁺Calculated lcms (esi): 591, 593 (3: 2), found 591, 593 (3: 2).

Step c:

to 4- [4- [ (iii) at room temperatureR) - (4, 5-dichloro-2-hydroxyphenyl) ([ ((ii) ((iii))S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidine-1-carbonyl]To a solution of piperazine-1-carboxylic acid tert-butyl ester (90 mg, 0.15 mmol) in 1, 4-dioxane (5 mL) was added aqueous HCl (6 mL)N2 mL). The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was dissolved in DCM (5 mL) and TFA (2 mL) was added at room temperature. The reaction solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column, 5 μm, 19X 150 mm; mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 5% B to 20% B in 7 minutes; a detector: UV 254/220 nm; retention time: 5.88 minutes. Collecting the fractions containing the desired product, concentrating under reduced pressure to obtain compound 141 (2- [ (2-)) as a purple solid R) -amino [1- (piperazine-1-carbonyl) piperidin-4-yl]Methyl radical]-4, 5-dichlorophenol trifluoroacetic acid) (89 mg, 79% of the two steps in total): C₁₇H₂₄Cl₂N₄O₂ [M + H]⁺Calculated lcms (esi): 387, 389 (3: 2), found 387, 389 (3: 2); ¹H NMR (400 MHz, CD₃OD) δ 7.43 (s, 1H), 7.08 (s, 1H), 4.16 (d, J = 9.7 Hz, 1H), 3.89 (d, J = 13.5 Hz, 1H), 3.72 (d, J = 13.4 Hz, 1H), 3.46 (t, J = 5.1 Hz, 4H), 3.24 (t, J = 5.1 Hz, 4H), 2.87 (dt, J = 30.4, 12.7 Hz, 2H), 2.30 (d, J = 11.1 Hz, 1H), 1.97 (d, J = 12.9 Hz, 1H), 1.45-1.19 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.10。

example 169 Compound 145 (, (R) -2- (amino (1- ((2-hydroxyethyl) sulfonyl) piperidin-4-yl) methyl) -4, 5-dichlorophenol trifluoroacetic acid)

Step a:

2- [ ((ii) under nitrogen atmosphere, stirred at 0 ℃ [ ((ii)R) -amino [1- (2-methoxyethanesulfonyl) piperidin-4-yl group]Methyl radical]To a solution of (e) -4, 5-dichlorophenol (free base of compound 132, example 165) (18 mg, 0.05 mmol) in DCM (2 mL) was added BBr₃(57 mg, 0.23 mmol). The resulting mixture was stirred at room temperature under nitrogen for 6 hours. The reaction was quenched with water (3 mL) at 0 ℃ and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: x select CSHOBD column 30X 150 mm 5 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 5% B to 30% B in 7 minutes; a detector: UV 220 nm; retention time: 6.65 minutes. Collecting the fractions containing the desired product, concentrating under reduced pressure to obtain compound 145 (2- [ (2- [)) as a light brown solid R) -amino [1- (2-hydroxyethanesulfonyl) piperidin-4-yl]Methyl radical]-4, 5-dichlorophenol trifluoroacetic acid) (11 mg, 63%): C₁₄H₂₀Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 383, 385 (3: 2), measured 383, 385 (3: 2); ¹H NMR (400 MHz, DMSO-d ₆) δ 10.94 (s, 1H), 8.26 (s, 3H), 7.60 (s, 1H), 7.10 (s, 1H), 5.02 (s, 1H), 4.24 (s, 1H), 3.73 (t, J = 6.3 Hz, 2H), 3.65 (d, J = 12.1 Hz, 1H), 3.55-3.48 (m, 2H), 3.16 (t, J = 6.3 Hz, 2H), 2.81-2.66 (m, 2H), 1.96 (t, J = 13.7 Hz, 2H), 1.4-1.23 (m, 1H), 1.22-1.12 (m, 1H)； ¹⁹F NMR (376 MHz, DMSO-d ₆) δ -73.61。

EXAMPLE 170 Compound 184 (1- [4- [ (4, 5-dichloro-2-hydroxyphenyl) (methylamino) methyl ] piperidin-1-yl ] -2, 3-dihydroxypropan-1-one trifluoroacetic acid)

Step a:

stirring 1- [4- [ (4, 5-dichloro-2-hydroxyphenyl) carbonyl group at 0 deg.C]Piperidin-1-yl radical]Ethan-1-one (intermediate 1, practice)Example 1) (2.60 g, 8.22 mmol) and K₂CO₃(2.30 g, 16.45 mmol) to a mixture in DMF (15 mL) was added iodomethane (2.3 g, 16.45 mmol) dropwise. The resulting mixture was stirred at room temperature for 16 hours. The reaction was quenched by the addition of water (30 mL) at 0 ℃. The resulting mixture was extracted with EtOAc (8X 40 mL). The combined organic layers were washed with brine (6X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 1- [4- [ (4, 5-dichloro-2-methoxyphenyl) carbonyl group]Piperidin-1-yl]Ethan-1-one. The crude product was used without further purification in the subsequent step: c₁₅H₁₇F₂NO₃ [M + H]⁺Calculated lcms (esi): 330, 332 (3: 2), found 330, 332 (3: 2);¹h NMR (300 MHz, M ethanol- d ₄) δ 7.64 (s, 1H), 7.35 (s, 1H), 4.48-4.34 (m, 1H), 3.95 (s, 3H), 3.90 (q, J = 3.4 Hz, 1H), 3.51 (tt, J = 10.8, 3.8 Hz, 1H), 3.23 (ddd, J = 14.0, 11.8, 2.9 Hz, 1H), 2.90 - 2.75 (m, 1H), 2.10 (s, 3H), 1.91 (dt, J = 13.6, 8.3 Hz, 2H), 1.69-1.38 (m, 2H)。

Step b:

1- [4- [ (4, 5-dichloro-2-methoxyphenyl) carbonyl group]Piperidin-1-yl radical]A solution of ethan-1-one (1.69 g, 1 eq.) in aqueous HCl (17 mL, 6N) was refluxed for 4 hours. The resulting mixture was concentrated in vacuo to give 4- [ (4, 5-dichloro-2-methoxyphenyl) carbonyl group as a yellow oil]Piperidine C₁₃H₁₅Cl₂NO₂ [M + H]⁺Calculated lcms (esi): 288, 290 (3: 2), found 288, 290 (3: 2).

Step c:

to a stirred solution of 2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid (0.48 g, 3.33 mmol) in DMF (4 mL) at room temperature were added EDCI (0.80 mg, 4.16 mmol) and HOBt (0.56 g, 4.16 mmol). To the above mixture was added 4- (4, 5-dichloro-2-methoxybenzoyl) piperidine (0.8 g, 2.77 mmol) and Et at room temperature₃N (0.84 g, 8.34 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 12 hours. The mixture was diluted with water (15 mL). The resulting mixture was extracted with EA (3X 25 mL).The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with a solution containing 10 mmol/L NH₄HCO₃Was eluted with 50% aqueous ACN solution to give 4- (4, 5-dichloro-2-methoxybenzoyl) -1- (2, 2-dimethyl-1, 3-dioxolane-4-carbonyl) piperidine (0.53 g, 39%) as a yellow oil ₁₉H₂₃Cl₂NO₅[M + H]⁺Calculated lcms (esi): 416, 418 (3: 2), found 416, 418 (3: 2).

Step d:

to a stirred mixture of 4- (4, 5-dichloro-2-methoxybenzoyl) -1- (2, 2-dimethyl-1, 3-dioxolane-4-carbonyl) piperidine (0.10 g, 0.24 mmol) and methylamine hydrochloride (81 mg, 1.20 mmol) in THF (2 mL) under a nitrogen atmosphere at room temperature was added Ti OEt in one portion₄(0.28 g, 1.20 mmol). The reaction mixture was stirred at 70 ℃ for 12 hours under nitrogen atmosphere. After cooling to room temperature, the NaBH is cooled at room temperature₄(18 mg, 0.48 mmol) was added to the above mixture. After the addition, the resulting mixture was stirred at room temperature for 1 hour. Reaction with H at room temperature₂O (40 mL) was quenched and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 50% aqueous ACN (plus 0.05% TFA) to give 1- [4- [ (4, 5-dichloro-2-methoxyphenyl) (methylamino) methyl ] amino as a yellow oil]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one (83 mg, 84%): C₁₇H₂₄Cl₂N₂O₄ [M + H]⁺Calculated lcms (esi): 391, 393 (3: 2), found 391, 393 (3: 2).

Step e:

1- [4- [ (4, 5-dichloro-2-methoxyphenyl) (methylamino) methyl ] amino stirred at 0 DEG C]Piperidin-1-yl](ii) -2, 3-Dihydroxypropan-1-one (60 mg, 0.15 mmol) in DCM (1 mL) was added BBr dropwise₃(0.5 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with MeOH (2 mL). Mixing the obtained mixtureConcentrating under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column 19X 150 mm, 5 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 5% B to 30% B in 7 minutes; a detector: UV 254/220 nm; retention time: 5.92 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure, and afforded compound 184 (1- [4- [ (4, 5-dichloro-2-hydroxyphenyl) (methylamino) methyl) as an off-white solid]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid) (16 mg, 21%): C₁₆H₂₂Cl₂N₂O₄ [M + H]⁺Calculated lcms (esi): 377, 379 (3: 2), found 377, 379 (3: 2); ¹H NMR (400 MHz, CD₃OD) δ 7.43 (s, 1H), 7.11 (s, 1H), 4.72-4.46 (m, 2H), 4.31-4.05 (m, 2H), 3.80-3.55 (m, 2H), 3.18-3.03 (m, 1H), 2.86-2.67 (m, 1H), 2.56 (s, 3H), 2.46 (s, 1H), 2.03 (d, J = 12.9 Hz, 1H), 1.45-1.13 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -76.95。

EXAMPLE 171 Compound 182 (1- [4- [ (4, 5-dichloro-2-hydroxyphenyl) (ethylamino) methyl ] piperidin-1-yl ] -2, 3-dihydroxypropan-1-one trifluoroacetic acid)

Step a:

to a stirred mixture of 4- (4, 5-dichloro-2-methoxybenzoyl) -1- (2, 2-dimethyl-1, 3-dioxolane-4-carbonyl) piperidine (step c, example 170) (0.10 g, 0.24 mmol) and ethylamine hydrochloride (97 mg, 1.20 mmol) in THF (2 mL) at room temperature was added Ti (OEt) ₄(0.27 g, 1.20 mmol). The reaction mixture was stirred at 70 ℃ for 12 hours under nitrogen atmosphere. After cooling to room temperature, NaBH is allowed to cool at room temperature₄(18 mg, 0.48 mmol) was added to the above mixture. The resulting mixture was stirred at room temperature for 1 hour. Reaction with H at room temperature₂O (40 mL) quench. The resulting mixture was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 3 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 30% aqueous ACN (plus 0.5% TFA). The fractions containing the desired product were collected and concentrated under reduced pressure to give 1- (4- ((4, 5-dichloro-2-methoxyphenyl) (ethylamino) methyl) piperidin-1-yl) -2, 3-dihydroxypropan-1-one (0.10 g, 74%) as a yellow oil C₂₁H₂₆Cl₂N₂O₄ [M + H]⁺Calculated lcms (esi): 405, 407 (3: 2), found 405, 407 (3: 2).

Step b:

to a stirred solution of 1- (4- ((4, 5-dichloro-2-methoxyphenyl) (ethylamino) methyl) piperidin-1-yl) -2, 3-dihydroxypropan-1-one (60 mg, 0.15 mmol) in DCM (1 mL) was added BBr dropwise at 0 deg.C₃(0.5 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with MeOH (2 mL). The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column 30X 150 mm, 5 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 5% B to 28% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.42 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure and afforded compound 182 (1- [4- [ (4, 5-dichloro-2-hydroxyphenyl) (ethylamino) methyl) as an off-white solid ]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid) (20 mg, 38%): C₁₇H₂₄Cl₂N₂O₄ [M + H]⁺Calculated lcms (esi): 391, 393 (3: 2), found 391, 393 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.43 (s, 1H), 7.09 (s, 1H), 4.71-4.43 (m, 2H), 4.30-4.05 (m, 2H), 3.74-3.56 (m, 2H), 3.07-2.82 (m, 3H), 2.75-2.53 (m, 1H), 2.50-2.36 (m, 1H), 2.05 (d, J = 12.9 Hz, 1H), 1.49-1.34 (m, 2H), 1.30 (t, J = 7.3 Hz, 3H), 1.24-1.09 (m, 1H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.05.

example 172 Compound 187 ((2)R)-1-[4-[(R) -amino (2, 3-dichloro-6-hydroxyphenyl) methyl group]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid)

Step a:

to stirred HOBt (48 mg, 0.36 mmol), EDCI (68 mg, 0.36 mmol) (5 mL) and (4) at room temperatureR) (2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid (52 mg, 0.36 mmol) in DMF was addedS)-N-[(R) - [ 23-dichloro-6- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.10 g, 0.24 mmol) and Et₃N (48 mg, 0.48 mmol). The reaction solution was stirred at room temperature under nitrogen atmosphere for 12 hours. The reaction was quenched with water (30 mL) at room temperature. The resulting mixture was extracted with EA (3X 20 mL). The combined organic layers were washed with brine (3X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to obtain (A) as a pale yellow oilS)-N-[(R) - [2, 3-dichloro-6- (prop-2-en-1-yloxy) phenyl]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]2-methylpropane-2-sulfinamide (0.23 g, 88%): C ₂₅H₃₆Cl₂N₂O₅S [M + H]⁺Lcms (esi) calculated value of (a): 547, 549 (3: 2), found 547, 549 (3: 2).

Step b:

stirring at room temperature (S)-N-[(R) - [2, 3-dichloro-6- (prop-2-en-1-yloxy) phenyl]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide (0.13 g, 0.24 mmol) and Pd (PPh)₃)₄ (27 mg, 0.02 mmol) in THF (2 mL) NaBH was added₄(18 mg, 0.48 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. To react with NH₄Aqueous Cl (5 mL) was quenched. Concentrating the resulting mixture under reduced pressure to obtain (A) as a light brown solidS)-N-[(R) - (2, 3-dichloro-6-hydroxyphenyl) ([1- [ (4) ]R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]2-methylpropane-2-sulfinamide (0.10 g, 66%): C₂₂H₃₂Cl₂N₂O₅S [M + H]⁺Calculated lcms (esi): 507, 509 (3: 2), found 507, 509 (3: 2).

Step c:

stirring at room temperature (S)-N-[(R) - (2, 3-dichloro-6-hydroxyphenyl) ([1- [ (4) ]R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide (0.10 g, 0.20 mmol) in THF (2 mL) aqueous HCl (4) was addedN1.5 mL). The resulting solution was stirred at room temperature for 30 minutes under nitrogen atmosphere. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: x Bridge Shield RP18 OBD column, 5 μm, 19X 150 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 5% B to 17% B in 7 minutes; a detector: UV 220/254 nm; retention time: 6.5 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 187 ((2) as an off-white solid R)-1-[4-[(R) -amino (2, 3-dichloro-6-hydroxyphenyl) methyl]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid) (37 mg, 38%): C₁₅H₂₀Cl₂N₂O₄ [M + H]⁺Lcms (esi) calculated value of (a): 363, 365 (3: 2), measured 363, 365 (3: 2); ¹H NMR (400 MHz, CD₃OD) δ 7.47 (d, J = 8.9 Hz, 1H), 6.92 (d, J = 8.9 Hz, 1H), 4.80-4.41 (m, 3H), 4.19 (dd, J = 66.7, 13.9 Hz, 1H), 3.79-3.54 (m, 2H), 3.20-2.95 (m, 1H), 2.87-2.44 (m, 2H), 2.07 (s, 1H), 1.55-1.16 (m, 3H)。

example 173 Compound 146 (, (R) -2- (amino (1- (6-aminopyridin-2-yl) piperidin-4-yl) methyl) -4, 5-dichlorophenol trifluoroacetic acid)

Step a:

stirring at room temperature (S)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]To a solution of-2-methylpropane-2-sulfinamide (0.20 g, 0.48 mmol) and 2-chloro-6-nitropyridine (0.13 g, 0.72 mmol) in DMSO (2 mL) was added K₂CO₃(0.13 g, 0.96 mmol). The reaction was allowed to warm to 80 ℃ and stirred for 2 hours. The resulting mixture was diluted with EA (20 mL) and water (20 mL). The partitioned aqueous solution was then extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC, eluting with PE/EA (1/1), to give (A) as a yellow solidS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (6-Nitropyridin-2-yl) piperidin-4-yl]Methyl radical]2-methylpropane-2-sulfinamide (0.12 g, 46%): C₂₄H₃₀Cl₂N₄O₄S [M + H]⁺Calculated lcms (esi): 541, 543 (3: 2), measured value 541, 543 (3: 2).

Step b:

under nitrogen atmosphere, stirring at room temperatureS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (6-Nitropyridin-2-yl) piperidin-4-yl]Methyl radical]-2-methylpropane-2-sulfinamide (0.12 g, 0.22 mmol) and Pd (PPh)₃)₄(2.56 mg, 0.002 mmol) in THF (1 mL) NaBH was added₄(16.77 mg, 0.44 mmol). After stirring at room temperature for 30 minutes under nitrogen atmosphere, the resulting mixture was quenched with water (2 mL) and concentrated under reduced pressure to give as a pale yellow solidN-[(R) - (4, 5-dichloro-2-hydroxyphenyl) [1- (6-nitropyridin-2-yl) piperidin-4-yl]Methyl radical]2-methylpropane-2-sulfinamide (0.11g, crude), which is used directly in the subsequent step without further purification C₂₁H₂₆Cl₂N₄O₄S [M + H]⁺Calculated lcms (esi): 501, 503 (3: 2), found 501, 503 (3: 2).

Step c:

will be provided withN-[(R) - (4, 5-dichloro-2-hydroxyphenyl) [1- (6-nitropyridin-2-yl) piperidin-4-yl]Methyl radical]2-methylpropane-2-sulfinylA solution of amine (0.11g, 0.22 mmol) in HCl (1 mL, 4M) and 1, 4-dioxane (1 mL) was stirred at room temperature for 1 hour. Purifying the obtained solution by reverse phase chromatography, eluting with 42% ACN water solution (plus 0.05% TFA) to obtain 2- [ ((R)) as yellow oilR) -amino [1- (6-nitropyridin-2-yl) piperidin-4-yl ]Methyl radical]-4, 5-dichlorophenol (75 mg, 80%): C₁₇H₁₈Cl₂N₄O₃ [M + H]⁺Calculated lcms (esi): 397, 399 (3: 2), found 397, 399 (3: 2);¹H NMR (400 MHz, DMSO-d ₆) δ 10.98 (s, 1H), 7.93-7.81 (m, 1H), 7.68-7.55 (m, 1H), 7.42 (d, J = 7.5 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 7.11 (d, J = 3.9 Hz, 1H), 4.49 (d, J = 13.4 Hz, 1H), 4.37-4.17 (m, 2H), 2.97-2.82 (m, 2H), 2.20 (d, J = 10.4 Hz, 1H), 2.03-1.88 (m, 1H), 1.38-1.22 (m, 3H)。

step d:

stirring of 2- [ (ii) at room temperatureR) -amino [1- (6-nitropyridin-2-yl) piperidin-4-yl]Methyl radical]-4, 5-dichlorophenol (75 mg, 0.19 mmol) and SnCl₂(0.36 g, 1.89 mmol) in MeOH (3 mL) aqueous HCl (12) was added N3 mL). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The residue was purified by reverse phase chromatography on column, C18; mobile phase, ACN in water (plus 0.05% TFA), gradient 5% -80% over 50 min; a detector: UV 210 nm to give compound 146 (2- [ (2- [)) as an off-white solidR) -amino [1- (6-aminopyridin-2-yl) piperidin-4-yl]Methyl radical]-4, 5-dichlorophenol trifluoroacetic acid) (35 mg, 50%): C₁₇H₂₀Cl₂N₄O [M + H]⁺Calculated lcms (esi): 367, 369 (3: 2), found 367, 369 (3: 2); ¹H NMR (400 MHz, DMSO-d ₆) δ 11.00 (s, 1H), 8.33 (s, 3H), 7.63 (s, 1H), 7.57 (br, 2H), 7.13 (s, 1H), 6.19-6.14 (m, 1H), 6.03 (s, 1H), 4.24 (s, 1H), 4.13 (d, J = 13.2 Hz, 1H), 3.95 (d, J = 13.3 Hz, 1H), 2.97-2.92 (m, 2H), 2.18 (d, J =10.5 hours z, 1H), 1.97 (d,J = 13.0 Hz, 1H), 1.31-1.21 (m, 3H)。

example 174 Compounds 147 (, (R) -2- (amino (1- (5-aminopyridin-2-yl) piperidin-4-yl) methyl) -4, 5-dichlorophenol trifluoroacetic acid)

Step a:

at room temperature toS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]To a solution of-2-methylpropane-2-sulfinamide (0.15 g, 0.36 mmol) and 5-bromo-2-fluoropyridine (94 mg, 0.54 mmol) in ACN (2 mL) was added K ₂CO₃(99 mg, 0.72 mmol). The reaction was warmed to 70 ℃ and stirred under nitrogen at the same temperature for 3 hours. The resulting mixture was diluted with water (30 mL) and extracted with EA (3X 20 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC, eluting with EA/PE (1/1), to give (A), (B), (C), (S)-N-[(R) - [1- (5-Bromopyridin-2-yl) piperidin-4-yl][4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]2-methylpropane-2-sulfinamide (0.15 g, 68%): C₂₄H₃₀BrCl₂N₃O₂S [M + H]⁺Calculated lcms (esi): 574, 576, 578, (2: 3: 1), found 574, 576, 578, (2: 3: 1).

Step b:

stirring at room temperature (S)-N-[(R) - [1- (5-Bromopyridin-2-yl) piperidin-4-yl][4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]-2-methylpropane-2-sulfinamide (60 mg, 0.10 mmol), methyl [2- (methylamino) ethyl]To a solution of amine (2 mg, 0.02 mmol) and trifluoroacetamide (24 mg, 0.21 mmol) in 1, 4-dioxane (3 mL) was added CuI (4 mg, 0.02 mmol) and Cs₂CO₃ (68 mg, 0.21 mmol). The resulting mixture was degassed three times with nitrogen and stirred at 100 ℃ for 12 hours under nitrogen atmosphere. After cooling to room temperature, the resulting mixture was diluted with water (5 mL) and extracted with EA (3X 25 mL). The combined organic layers were washed with brine (3X 15 mL), By anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give (A) as an off-white solidS)-N-[(R) - [1- (5-Aminopyridin-2-yl) piperidin-4-yl group][4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]2-methylpropane-2-sulfinamide (60 mg, 89%): C₂₄H₃₂Cl₂N₄O₂S [M + H]⁺Calculated lcms (esi): 511, 513 (3: 2), found 511, 513 (3: 2).

Step c:

stirring under nitrogen atmosphere at room temperatureS)-N-[(R) - [1- (5-Aminopyridin-2-yl) piperidin-4-yl group][4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]-2-methylpropane-2-sulfinamide (60 mg, 0.12 mmol) and Pd (PPh)₃)₄ (27 mg, 0.02 mmol) in THF (2 mL) NaBH was added₄ (9 mg, 0.24 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction was quenched with saturated NH at room temperature₄Aqueous Cl (3 mL) was quenched and concentrated under reduced pressure to give (A) as an off-white solidS)-N-[(R) - [1- (5-Aminopyridin-2-yl) piperidin-4-yl group](4, 5-dichloro-2-hydroxyphenyl) methyl group]2-methylpropane-2-sulfinamide (50 mg, crude), which is used directly in the subsequent step without further purification C₂₁H₂₈Cl₂N₄O₂S [M + H]⁺Calculated lcms (esi): 471, 473 (3: 2), found 471, 473 (3: 2).

Step d:

stirring at room temperature ( S)-N-[(R) - [1- (5-Aminopyridin-2-yl) piperidin-4-yl](4, 5-dichloro-2-hydroxyphenyl) methyl group](iii) solution of (E) -2-methylpropane-2-sulfinamide (50 mg, 0.11 mmol) in 1, 4-dioxane (2 mL) was added aqueous HCl (4)N1 mL). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: x select CSHOBD column 30X 150 mm 5 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 5% B to 25% B in 7 minutes; a detector: UV 220 nm; retention time:6.25 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure to give compound 147 ((R) -2- (amino (1- (5-aminopyridin-2-yl) piperidin-4-yl) methyl) -4, 5-dichlorophenol trifluoroacetic acid) (15 mg, 38% two-step total): C₁₇H₂₀Cl₂N₄O [M + H]⁺Calculated lcms (esi): 367, 369 (3: 2), found 367, 369 (3: 2); ¹H NMR (400 MHz, DMSO-d ₆) δ 11.96 (s, 1H), 11.1-10.9 (m, 1H), 8.30 (s, 3H), 7.68-7.56 (m, 2H), 7.41 (s, 2H), 7.12 (d, J = 2.2 Hz, 1H), 6.26 (dd, J = 7.0, 1.9 Hz, 1H), 6.00 (s, 1H), 4.24 (s, 1H), 3.92 (d, J = 13.2 Hz, 1H), 3.74 (d, J = 13.3 Hz, 1H), 3.09-2.89 (m, 2H), 2.25-2.12 (m, 1H), 1.97 (d, J = 13.0 Hz, 1H), 1.36-1.28 (m, 2H), 1.28-1.11 (m, 1H)； ¹⁹F NMR (376 MHz, DMSO-d ₆) δ -73.48.

EXAMPLE 175 Compound 148 (1- [4- [ (()R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]Azetidine-3-ol trifluoroacetic acid)

Step a:

stirring under nitrogen atmosphere at room temperatureS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.20 g, 0.48 mmol) and Et₃To a solution of N (96 mg, 0.95 mmol) in DCM (3 mL) was added 4-nitrophenylcarbonyl chloride (0.11 g, 0.57 mmol). The resulting mixture was stirred at room temperature under nitrogen for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 80% aqueous ACN (plus 0.05% TFA) to give 4- [ ((r)) as a pale yellow solidR) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]4-Nitrophenyl piperidine-1-carboxylate (0.12 g, 43%): C₂₆H₃₁Cl₂N₃O₆S [M + H]⁺Calculated lcms (esi): 584, 586 (3: 2), measured 584, 586 (3: 2).

Step b:

4-Nitrophenyl 4- [ (ii) to stirring at room temperatureR) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]To a solution of piperidine-1-carboxylate (0.30 g, 0.51 mmol) and azetidin-3-ol (0.11 g, 1.54 mmol) in DMF (4 mL) was added K₂CO₃ (0.14 g, 1.03 mmol). The reaction mixture was irradiated with microwave radiation at 150 ℃ for 30 minutes. The resulting mixture was filtered. The filtrate was purified by reverse phase chromatography, eluting with 50% aqueous ACN (plus 0.05% TFA) and obtained as a pale yellow solid ( S)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (3-Hydroxyazetidine-1-carbonyl) piperidin-4-yl]Methyl radical]2-methylpropane-2-sulfinamide (0.19 g, 71%): C₂₃H₃₃Cl₂N₃O₄S [M + H]⁺Calculated lcms (esi): 518, 520 (3: 2), found 518, 520 (3: 2).

Step c:

stirring under nitrogen at room temperatureS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (3-Hydroxyazetidine-1-carbonyl) piperidin-4-yl]Methyl radical]-2-methylpropane-2-sulfinamide (0.10 g, 0.19 mmol) and Pd (PPh)₃)₄(22 mg, 0.02 mmol) in THF (5 mL) NaBH was added₄(14 mg, 0.38 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. The resulting mixture was quenched with water (50 mL) at room temperature and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give a crude productN-[(R) - (4, 5-dichloro-2-hydroxyphenyl) [1- (3-hydroxyazetidin-1-carbonyl) piperidin-4-yl]Methyl radical]2-methylpropane-2-sulfinamide (50 mg, crude), which was used in the subsequent step without further purification C₂₀H₂₉Cl₂N₃O₄S [M + H]⁺Calculated lcms (esi): 478, 480 (3: 2), found 478, 480 (3 : 2)。

Step d:

will be provided with N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) [1- (3-hydroxyazetidine-1-carbonyl) piperidin-4-yl]Methyl radical]-2-methylpropane-2-sulfinamide (50 mg, 0.11 mmol) and aqueous HCl (6 mmol)N0.5 mL) in 1, 4-dioxane (1 mL) was stirred at room temperature for 30 minutes. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column, 5 μm, 19X 150 mm; a mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 5% B to 30% B in 7 minutes; a detector: UV 220 nm; retention time: 5.6 minutes. Collecting the fractions containing the desired product and concentrating under reduced pressure to obtain compound 148 (1- [4- [ (1-)) as a purple solidR) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]Azetidin-3-ol trifluoroacetic acid) (5 mg, 10% of two steps in total): C₁₆H₂₁Cl₂N₃O₃ [M + H]⁺Calculated lcms (esi): 374, 376 (3: 2), found 374, 376 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.45 (s, 1H), 7.10 (s, 1H), 5.27-5.20 (m, 1H), 4.35-4.07 (m, 2H), 4.06-3.55 (m, 5H), 3.32-3.06 (m, 2H), 2.50-2.40 (m, 1H), 2.15-2.03 (m, 1H), 1.53-1.45 (m, 2H), 1.41-1.36 (m, 1H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.00.

example 176. Compound 149 (2- [ (()R) -amino [1- (1)H-pyrazol-4-yl) piperidin-4-yl]Methyl radical]-4, 5-dichlorophenol trifluoroacetic acid)

Step a:

stirring under nitrogen atmosphere at room temperatureS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.15 g, 0.36 mmol) and 4-iodo-1- (triphenylmethyl) -1H-pyrazole (0.19 g, 0.43 mmol) in DMSO (3 mL) was added Cs₂CO₃(0.35 g, 1.07 mmol), L-proline (16 mg, 0.14 mmol) and CuI (14 mg, 0.07 mmol). The resulting mixture was degassed three times with nitrogen and stirred under nitrogen at 120 ℃ for 24 hours. After cooling to room temperature, the reaction mixture was diluted with water (30 mL) and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 65% aqueous ACN (plus 0.05% TFA) to give (a) as a pale yellow oilS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([1- [1- (triphenylmethyl) -1)H-pyrazol-4-yl]Piperidin-4-yl radical]) Methyl radical]2-methylpropane-2-sulfinamide (30 mg, 9%): C₄₁H₄₄Cl₂N₄O₂S [M + H]⁺Calculated lcms (esi): 727, 729 (3: 2), found 727, 729 (3: 2).

Step b:

stirring under nitrogen atmosphere at room temperatureS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([1- [1- (triphenylmethyl) -1)H-pyrazol-4-yl]Piperidin-4-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide (30 mg, 0.04 mmol) and Pd (PPh) ₃)₄(5 mg, 0.004 mmol) in THF (1 mL) NaBH was added₄(3 mg, 0.08 mmol). The resulting mixture was stirred at room temperature for 1 hour. Reacting with saturated NH₄Aqueous Cl (1 mL) was quenched at room temperature and concentrated under reduced pressure to give (A) as a brown solidS)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) ([1- [1- (triphenylmethyl) -1)H-pyrazol-4-yl]Piperidin-4-yl radical]) Methyl radical]2-methylpropane-2-sulfinamide (30 mg, crude), which was used in the next step without further purification: c₃₈H₄₀Cl₂N₄O₂S [M + H]⁺Calculated lcms (esi): 687, 689 (3: 2), found 687, 689 (3: 2);

step c:

stirring at room temperature (S)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) ([1- [1- (triphenylmethyl) -1)H-pyrazol-4-yl]Piperidin-4-yl radical]) Methyl radical]-2-methylTo a solution of propane-2-sulfinamide (30 mg, 0.04 mmol) in 1, 4-dioxane (1 mL) was added aqueous HCl (4%N1 mL). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xselect CSH OBD column 30 × 150 mm, 5 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 5% B to 20% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.28 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure, and compound 149 (2- [ (2) as a pale yellow solid) was obtained R) -amino [1- (1)H-pyrazol-4-yl) piperidin-4-yl]Methyl radical]-4, 5-dichlorophenol trifluoroacetic acid) (4.4 mg, 23% of two steps in total): C₁₅H₁₈Cl₂N₄O [M + H]⁺Calculated lcms (esi): 341, 343 (3: 2), found 341, 343 (3: 2); ¹H NMR (400 MHz, CD₃OD) δ 7.74 (s, 2H), 7.49 (s, 1H), 7.11 (s, 1H), 4.27 (d, J = 9.7 Hz, 1H), 3.77 (d, J = 12.3 Hz, 1H), 3.62-3.52 (m, 1H), 3.20-3.02 (m, 2H), 2.47-2.30 (m, 1H), 2.21 (d, J = 13.7 Hz, 1H), 1.83-1.69 (m, 1H), 1.69-1.47 (m, 2H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.11。

example 177. Compound 150 (, (R) -2- (amino (1- (4-aminopyridin-2-yl) piperidin-4-yl) methyl) -4, 5-dichlorophenol trifluoroacetic acid)

Step a:

stirring at room temperature (S)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl](ii) -2-methylpropane-2-sulfinamide (80 mg, 0.20 mmol) and 5-bromo-2-fluoropyridine (0.17 g, 0.96 mmol) in ACN (3 mL) to which K was added₂CO₃ (53 mg, 0.38 mmol). The resulting mixture was stirred at 70 ℃ for 16 hours under nitrogen atmosphere. After cooling to room temperature, the resulting mixture was diluted with water (40 mL) and extracted with EA (3X 30 mL). The combined organic matterThe layer was washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC, eluting with PE/EA (1/2), to give (A) as an off-white solidS)-N-[(R) - [1- (5-Bromopyridin-2-yl) piperidin-4-yl][4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]-2-methylpropane-2-sulfinamide (60 mg, 49%): C₂₄H₃₀BrCl₂N₃O₂S [M + H]⁺Calculated lcms (esi): 574, 576, 578 (2: 3: 1), found 574, 576, 578 (2: 3: 1).

Step b:

stirring at room temperature (S)-N-[(R) - [1- (4-Bromopyridin-2-yl) piperidin-4-yl][4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]-2-methylpropane-2-sulfinamide (60 mg, 0.10 mmol), methyl [2- (methylamino) ethyl]To a solution of amine (1.9 mg, 0.02 mmol) and trifluoroacetamide (24 mg, 0.21 mmol) in 1, 4-dioxane (3 mL) was added CuI (4 mg, 0.02 mmol) and Cs₂CO₃ (68 mg, 0.21 mmol). The resulting mixture was degassed three times with nitrogen atmosphere and stirred at 100 ℃ for 12 hours under nitrogen atmosphere. The resulting mixture was diluted with water (20 mL) and extracted with EA (3X 25 mL). The combined organic layers were washed with brine (3X 5 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give (A) as an off-white solidS)-N-[(R) - [1- (4-Aminopyridin-2-yl) piperidin-4-yl group][4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]2-methylpropane-2-sulfinamide (60 mg, 89%): C₂₄H₃₂Cl₂N₄O₂S [M + H]⁺Calculated lcms (esi): 511, 513, (3: 2), found 511, 513, (3: 2).

Step c:

stirring at room temperature (S)-N-[(R) - [1- (4-Aminopyridin-2-yl) piperidin-4-yl group][4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]-2-methylpropane-2-sulfinamide (60 mg, 0.12 mmol) and Pd (PPh) ₃)₄ (27 mg, 0.02 mmol) in THF (3 mL) NaBH was added₄ (8.9 mg, 0.24mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. Reacting with saturated NH₄Aqueous Cl (3 mL) was quenched at room temperature and concentrated under reduced pressure. The residue was purified by reverse phase chromatography with 55% aqueous ACN (plus 0.05% TFA) to give (a) as a pale yellow solidS)-N-[(R) - [1- (4-Aminopyridin-2-yl) piperidin-4-yl group](4, 5-dichloro-2-hydroxyphenyl) methyl group]2-methylpropane-2-sulfinamide (50 mg, 54%): C₂₁H₂₈Cl₂N₄O₂S [M + H]⁺Calculated lcms (esi): 471, 473, (3: 2), found 471, 473, (3: 2).

Step d:

stirring at room temperature (S)-N-[(R) - [1- (4-Aminopyridin-2-yl) piperidin-4-yl group](4, 5-dichloro-2-hydroxyphenyl) methyl group](iii) -2-methylpropane-2-sulfinamide (50 mg, 0.11 mmol) in 1, 4-dioxane (2 mL) to which was added aqueous HCl (4)N1 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: x select CSHOBD column 30X 150 mm 5. mu. m n; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 7% B to 23% B in 7 minutes; a detector: UV 220 nm; retention time: 6.13 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 150 ((R) -2- (amino (1- (4-aminopyridin-2-yl) piperidin-4-yl) methyl) -4, 5-dichlorophenol trifluoroacetic acid) (20 mg, 37%) as an off-white solid, C ₁₇H₂₀Cl₂N₄O [M + H]⁺Lcms (esi) calculated value of (a): 367, 369 (3: 2), found 367, 369 (3: 2); ¹H NMR (400 MHz, CD₃OD) δ 7.53 (d, J =7.2 Hz, 1H), 7.46 (s, 1H), 7.10 (s, 1H), 6.32 (dd, J = 7.1, 2.1 Hz, 1H), 6.08 (d, J = 2.1 Hz, 1H), 4.20 (d, J = 9.9 Hz, 1H), 4.02 (d, J = 13.4 Hz, 1H), 3.86 (d, J = 13.5 Hz, 1H), 3.11 (d, J = 12.6 Hz, 1H), 3.07-2.95 (m, 1H), 2.51-2.41 (m, 1H), 2.12 (d, J = 13.3 Hz, 1H), 1.60-1.30 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -76.94.

example 178 Compound 151 (2- [ (2- [))R) -amino [1- (5-amino-1, 3, 4-thiadiazol-2-yl) piperidin-4-yl]Methyl radical]-4, 5-dichlorophenol trifluoroacetic acid)

Step a:

under nitrogen atmosphere, at 80 ℃: (S)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.10 g, 0.24 mmol), 5-bromo-1, 3, 4-thiadiazol-2-amine (52 mg, 0.29 mmol) and K₂CO₃A mixture of (66 mg, 0.48 mmol) in ACN (3 mL) was stirred for 6 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by preparative TLC, eluting with PE/EA (1/2), to give (A) as a pale yellow solidS)-N-[(R) - [1- (5-amino-1, 3, 4-thiadiazol-2-yl) piperidin-4-yl group][4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]2-methylpropane-2-sulfinamide (0.11 g, 71%): C₂₁H₂₉Cl₂N₅O₂S₂ [M + H⁺]⁺Calculated lcms (esi): 518, 520 (3: 2), found 518, 520 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.24 (s, 1H), 6.98 (s, 1H), 6.10-5.96 (m, 1H), 5.40 (dd, J =21.4, 13.8 Hz, 2H), 4.61-4.65 (m, 2H), 4.47-4.39 (m, 1H), 3.98-3.90 (m, 1H), 3.77 (d, J = 12.6 Hz, 2H), 3.05-2.84 (m, 2H), 2.12 (d, J = 13.4 Hz, 2H), 1.47-1.43 (m, 1H), 1.39-1.20 (m, 2H), 1.16 (s, 9H)。

step b:

stirring at room temperature under nitrogen (S)-N-[(R) - [1- (5-amino-1, 3, 4-thiadiazol-2-yl) piperidin-4-yl group][4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]-2-methylpropane-2-sulfinamide (0.10 g, 0.21 mmol) and Pd (PPh)₃)₄(48 mg, 0.04 mmol) in THF (5 mL) NaBH was added ₄(16 mg, 0.42 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. Mixing the obtained mixture withWater (50 mL) was quenched at room temperature and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give crude (A) as a brown solidS)-N-[(R) - [1- (5-amino-1, 3, 4-thiadiazol-2-yl) piperidin-4-yl](4, 5-dichloro-2-hydroxyphenyl) methyl group]2-methylpropane-2-sulfinamide, which is used directly in the subsequent step without further purification C₁₈H₂₅Cl₂N₅O₂S₂ [M + H]⁺Calculated lcms (esi): 478, 480 (3: 2), found 478, 480 (3: 2).

Step c:

stirring at room temperature (S)-N-[(R) - [1- (5-amino-1, 3, 4-thiadiazol-2-yl) piperidin-4-yl group](4, 5-dichloro-2-hydroxyphenyl) methyl group]-2-methylpropane-2-sulfinamide (0.10 g, crude) in 1, 4-dioxane (5 mL) aqueous HCl (6) was addedN3 mL). The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: an X select CSH OBD column 30X 150 mm 5μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 5% B to 23% B in 7 minutes; a detector: UV 220 nm; retention time: 6.48 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 151 (2- [ (2-)) as a purple solid R) -amino [1- (5-amino-1, 3, 4-thiadiazol-2-yl) piperidin-4-yl]Methyl radical]-4, 5-dichlorophenol trifluoroacetic acid) (37 mg, 47% in total) C₁₄H₁₇Cl₂N₅OS [M + H]⁺Lcms (esi) calculated value of (a): 374, 376 (3: 2), found 374, 376 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.45 (s, 1H), 7.09 (s, 1H), 4.20 (d, J = 9.9 Hz, 1H), 3.90 (d, J = 13.1 Hz, 1H), 3.71 (d, J = 13.0 Hz, 1H), 3.22-3.01 (m, 2H), 2.40-2.36 (m, 1H), 2.02-2.10 (m, 1H), 1.51-1.57 (m, 1H), 1.46-1.30 (m, 2H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.09。

example 179 Compound 154 (2- [ (()R)-Amino [1- (1)H-pyrazol-3-yl) piperidin-4-yl]Methyl radical]-4, 5-dichlorophenol trifluoroacetic acid)

Step a:

stirring under nitrogen atmosphere at room temperatureS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.25 g, 0.60 mmol) and 3-iodo-1- (triphenylmethyl) -1H-pyrazole (0.31 g, 0.72 mmol) in DMSO (3 mL) was added Cs₂CO₃(0.58 g, 1.79 mmol), L-proline (27 mg, 0.24 mmol) and CuI (23 mg, 0.12 mmol). The resulting mixture was stirred at 120 ℃ for 24 hours under nitrogen atmosphere. After cooling to room temperature, the reaction solution was diluted with water (30 mL) and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 65% aqueous ACN (plus 0.05% TFA) to give (a) as a pale yellow oilS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ]([1- [1- (triphenylmethyl) -1-)H-pyrazol-3-yl]Piperidin-4-yl]) Methyl radical]-2-methylpropane-2-sulfinamide (50 mg, 8%): C₄₁H₄₄Cl₂N₄O₂S [M + H]⁺Lcms (esi) calculated value of (a): 727, 729 (3: 2), found 727, 729 (3: 2).

Step b:

stirring under nitrogen at room temperatureS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([1- [1- (triphenylmethyl) -1H-pyrazol-3-yl)]Piperidin-4-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide (50 mg, 0.07 mmol) and Pd (PPh)₃)₄(8 mg, 0.01 mmol) in THF (1 mL) NaBH was added₄(5 mg, 0.14 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated NH at room temperature₄Aqueous Cl (1 mL) was quenched and concentrated under reduced pressure to give a brown solidTo (a)S)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) ([1- [1- (triphenylmethyl) -1)H-pyrazol-3-yl]Piperidin-4-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide (50 mg, crude), which was used directly in the next step without further purification: c₃₈H₄₀Cl₂N₄O₂S [M + H]⁺Calculated lcms (esi): 687, 689 (3: 2), found 687, 689 (3: 2);

step c:

stirring at room temperature (S)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) ([1- [1- (triphenylmethyl) -1)H-pyrazol-3-yl]Piperidin-4-yl radical]) Methyl radical](iii) -2-methylpropane-2-sulfinamide (50 mg, 0.07 mmol) in 1, 4-dioxane (1 mL) to which was added aqueous HCl (4) N1 mL). The reaction solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xselect CSH OBD column 30X 150 mm 5 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 5% B to 28% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.65 minutes. Collecting the fractions containing the desired product, concentrating under reduced pressure to obtain compound 154 (2- [ (2-)) as a purple solidR) -amino [1- (1)H-pyrazol-3-yl) piperidin-4-yl]Methyl radical]-4, 5-dichlorophenol trifluoroacetic acid) (2.4 mg, 8% of two steps in total): C₁₅H₁₈Cl₂N₄O [M + H]⁺Calculated lcms (esi): 341, 343 (3: 2), found 341, 343 (3: 2); ¹H NMR (400 MHz, CD₃OD) δ 7.64 (s, 1H), 7.45 (s, 1H), 7.09 (s, 1H), 5.90 (s, 1H), 4.18 (d, J = 9.8 Hz, 1H), 3.84 (d, J = 12.5 Hz, 1H), 3.68 (d, J = 12.5 Hz, 1H), 2.89 (td, J =12.6, 2.9 Hz, 1H), 2.83-2.70 (m, 1H), 2.33-2.21 (m, 1H), 2.08-1.99 (m, 1H), 1.60-1.48 (m, 1H), 1.44-1.30 (m, 2H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.09。

example 180 Compound 158 (2- [ (2))R) -amino [1- (1)H-pyrazole-4-sulfonyl) piperidin-4-yl]Methyl radical]-4, 5-dichlorophenol trifluoroacetic acid)

Step a:

stirring at 0 ℃ under nitrogen atmosphere (S)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide (50 mg, 0.12 mmol) and Et₃To a solution of N (24 mg, 0.24 mmol) in DCM (1 mL) was added 1HPyrazole-4-sulfonyl chloride (20 mg, 0.12 mmol). The resulting solution was stirred at 0 ℃ for 1 hour under nitrogen atmosphere. The resulting solution was quenched with water (50 mL) and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 55% aqueous ACN (plus 0.05 TFA) to give (a) as a pale yellow oilS)- N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1-(1H-pyrazole-4-sulfonyl) piperidin-4-yl]Methyl radical]-2-methylpropane-2-sulfinamide (70 mg, 85%): C₂₂H₃₀Cl₂N₄O₄S₂ [M + H]⁺Calculated lcms (esi): 549, 551 (3: 2), found 549, 551 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.88 (s, 2H), 7.20 (s, 1H), 6.97 (s, 1H), 6.11-5.86 (m, 1H), 5.46-5.22 (m, 2H), 4.67-4.07 (m, 3H), 3.85-3.71 (m, 2H), 2.18 (t, J = 11.5 Hz, 2H), 2.09 (d, J =13.2 Hz, 1H), 1.79-1.68 (m, 1H), 1.61-1.27 (m, 3H), 1.16 (s, 9H)。

step b:

stirring under nitrogen atmosphere at room temperatureS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1-(1H-pyrazole-4-sulfonyl) piperidin-4-yl]Methyl radical]-2-methylpropane-2-sulfinamide (70 mg, 0.13 mmol) and Pd (PPh)₃)₄(1.5 mg, 0.001 mmol) in THF (1 mL) NaBH was added₄(10 mg, 0.26 mmol). After stirring at room temperature for 30 minutes under nitrogen, the resulting mixture was taken up with saturated NH₄Aqueous Cl solution(1 mL) quench and concentrate under reduced pressure to give (A) as a brown solidS)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) [1- (1)H-pyrazole-4-sulfonyl) piperidin-4-yl]Methyl radical]-2-methylpropane-2-sulfinamide (70 mg, crude), which was used in the next step without further purification: c₁₉H₂₆Cl₂N₄O₄S₂ [M + H]⁺Calculated lcms (esi): 509, 511 (3: 2), found 509, 511 (3: 2).

Step c:

stirring at room temperature (S)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) [1- (1)H-pyrazole-4-sulfonyl) piperidin-4-yl]Methyl radical](iii) mixture of (E) -2-methylpropane-2-sulfinamide (70 mg, 0.14 mmol) in 1, 4-dioxane (1 mL) aqueous HCl (4) was addedN1 mL). The resulting mixture was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xselect CSH OBD column 30X 150 mm 5 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 11% B to 31% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.68 minutes. Collecting the fractions containing the desired product, concentrating under reduced pressure to obtain compound 158 (2- [ (2-)) as a purple solidR) -amino [1- (1)H-pyrazole-4-sulfonyl) piperidin-4-yl]Methyl radical]-4, 5-dichlorophenol trifluoroacetic acid) (49.9 mg, 75% of two steps in total): C₁₅H₁₈Cl₂N₄O₃S [M + H]⁺Calculated lcms (esi): 405, 407 (3: 2), found 405, 407 (3: 2);¹H NMR (400 MHz, CD₃OD) ¹H NMR δ 8.00 (s, 2H), 7.42 (s, 1H), 7.06 (s, 1H), 4.16 (d, J = 9.7 Hz, 1H), 3.91-3.78 (m, 1H), 3.75-3.67 (m, 1H), 2.23-2.10 (m, 2H), 2.12-1.97 (m, 2H), 1.57-1.45 (m, 1H), 1.45-1.28 (m, 2H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.06。

example 181 Compound 180 (4- [4- [ (S))R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidin-1-yl radical]-1, 2-dihydropyridin-2-one trifluoroacetic acid)

Step a:

stirring at room temperature (S)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ](piperidin-4-yl) methyl](ii) -2-methylpropane-2-sulfinamide (80 mg, 0.19 mmol) and 4-fluoro-1, 2-dihydropyridin-2-one (32 mg, 0.29 mmol) in ACN (1 mL) to which K was added₂CO₃ (53 mg, 0.38 mmol). The reaction was stirred at 80 ℃ for 4 hours. After cooling to room temperature, the resulting mixture was filtered. The filtrate was purified by reverse phase chromatography, eluting with 45% aqueous ACN (plus 0.05% TFA) and obtained as an off-white solid (S)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (2-oxo-1, 2-dihydropyridin-4-yl) piperidin-4-yl group]Methyl radical]2-methylpropane-2-sulfinamide (90 mg, 92%): C₂₄H₃₁Cl₂N₃O₃S [M + H]⁺Calculated lcms (esi): 512, 514 (3: 2), found 512, 514 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.48 (s, 1H), 7.20 (s, 1H), 7.01 (s, 1H), 6.46-6.31 (m, 1H), 6.13-5.93 (m, 2H), 5.48-5.28 (m, 2H), 4.59 (s, 2H), 4.38-4.30 (m, 2H), 4.08-3.88 (m, 2H), 3.08-2.80 (m, 2H), 2.31-2.02 (m, 2H), 1.60-1.42 (m, 1H), 1.42-1.24 (m, 2H), 1.17 (s, 9H)。

step b:

stirring at room temperature (S)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (2-oxo-1, 2-dihydropyridin-4-yl) piperidin-4-yl group]Methyl radical]-2-methylpropane-2-sulfinamide (90 mg, 0.18 mmol) and Pd (PPh)₃)₄(2 mg, 0.002 mmol) in THF (2 mL) NaBH was added₄(13 mg, 0.35 mmol). The reaction was stirred at room temperature for 0.5 h. Reacting with saturated NH₄Aqueous Cl (1 mL) was quenched and concentrated under reduced pressure to give (A) as a brown solidS)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) [1- (2-oxo-1, 2-dihydropyridin-4-yl) piperidin-4-yl ]Methyl radical]2-methylpropane-2-sulfinamide (90 mg, crude), which did not go furtherOne step purification was used directly in the next step: c₂₁H₂₇Cl₂N₃O₃S [M + H]⁺Calculated lcms (esi): 472, 474 (3: 2), found 472, 474 (3: 2).

Step c:

stirring at room temperature (S)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) [1- (2-oxo-1, 2-dihydropyridin-4-yl) piperidin-4-yl]Methyl radical](iii) -2-methylpropane-2-sulfinamide (90 mg, 0.19 mmol) in 1, 4-dioxane (1 mL) to which was added aqueous HCl (4)N1 mL). The reaction was stirred at room temperature for 0.5 h. The reaction was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: x select CSH OBD column 30X 150 mm 5 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 5% B to 28% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.42 minutes. Collecting the fractions containing the desired product, concentrating under reduced pressure to obtain compound 180 (4- [4- [ (4- [)) in the form of light green syrupR) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidin-1-yl radical]-1, 2-dihydropyridin-2-one trifluoroacetic acid) (46 mg, 55% of a two-step total): C₁₇H₁₉Cl₂N₃O₂ [M + H]⁺Calculated lcms (esi): 368, 370 (3: 2), found 368, 370 (3: 2); ¹H NMR (400 MHz, CD₃OD) δ 7.51-7.41 (m, 2H), 7.09 (s, 1H), 6.51 (d, J = 7.7 Hz, 1H), 5.94 (d, J = 2.6 Hz, 1H), 4.21-4.08 (m, 2H), 4.02 (d, J = 13.9 Hz, 1H), 3.17-2.89 (m, 2H), 2.50-2.38 (m, 1H), 2.11-2.01 (m, 1H), 1.53-1.38 (m, 2H), 1.37-1.20 (m, 1H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.12。

Example 182 Compound 183 ((2- [))R) -amino [1- (5-amino-1, 2, 4-oxadiazol-3-yl) piperidin-4-yl]Methyl radical]-4, 5-dichlorophenol))

Step a:

at room temperature toS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]To a solution of-2-methylpropane-2-sulfinamide (0.30 g, 0.72 mmol) in ACN (2 mL) was added cyano (diphenoxymethylene) amine (0.34 g, 1.43 mmol). The reaction solution was stirred at 70 ℃ for 3 hours. After cooling to room temperature, the resulting solution was concentrated under reduced pressure. The residue was purified by preparative TLC, eluting with EA/PE (2/1), to give (A) as an off-white solidN-cyano-4- [ ((iii))R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidine-1-carboximidanyl phenyl ester) (70 mg, 17%): C₂₇H₃₂Cl₂N₄O₃S [M + H]⁺Calculated lcms (esi): 563, 565 (3: 2), found 563, 565 (3: 2).

Step b:

at room temperature toN-cyano-4- [ ((iii))R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]piperidine-1-Methylenephenylimidate) (65 mg, 0.12 mmol) in DMF (1 mL) NH was added₂OH HCl (48 mg, 0.69 mmol) and DIEA (0.15 g, 1.15 mmol). The reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with water (20 mL) and extracted with EA (3X 25 mL). The combined organic layers were washed with brine (2X 15 mL) and dried over anhydrous Na ₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with DCM/MeOH (20/1) to give (A) as an off-white solidS)-N-[(R) - [1- (5-amino-1, 2, 4-oxadiazol-3-yl) piperidin-4-yl group][4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]2-methylpropane-2-sulfinamide (19 mg, 36%): C₂₁H₂₉Cl₂N₅O₃S [M + H]⁺Calculated lcms (esi): 502, 504 (3: 2), found 502, 504 (3: 2).

Step c:

stirring under nitrogen atmosphere at room temperatureS)-N-[(R) - [1- (5-amino-1, 2, 4-oxadiazol-3-yl) piperidin-4-yl group][4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]-2-methylPropane-2-sulfinamide (0.10 g, 0.20 mmol) and Pd (PPh)₃)₄ (23 mg, 0.02 mmol) in THF (2 mL) NaBH was added₄ (15 mg, 0.40 mmol). The reaction mixture was stirred at room temperature for 30 minutes under nitrogen atmosphere. The resulting mixture was quenched with water (50 mL) at room temperature and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give crude product (A)S)-N-[(R) - [1- (5-amino-1, 2, 4-oxadiazol-3-yl) piperidin-4-yl group](4, 5-dichloro-2-hydroxyphenyl) methyl group]-2-methylpropane-2-sulfinamide. The crude product was used without further purification in the subsequent step: c ₂₁H₂₉Cl₂N₅O₃S [M + H]⁺Lcms (esi) calculated value of (a): 462, 464 (3: 2), found 462, 464 (3: 2).

Step d:

stirring at 0 ℃: (S)-N-[(R) - [1- (5-amino-1, 2, 4-oxadiazol-3-yl) piperidin-4-yl](4, 5-dichloro-2-hydroxyphenyl) methyl group](iii) -2-methylpropane-2-sulfinamide (80 mg, 0.17 mmol) in 1, 4-dioxane (2 mL) to which was added aqueous HCl (4)N0.8 mL). The reaction solution was stirred at 0 ℃ for 30 minutes. The solution was saturated with NaHCO₃The aqueous solution was neutralized to pH 7. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD column 30X 150 mm, 5 μm; mobile phase A: having a NH concentration of 10 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 30% B to 50% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.5 minutes. Collecting the fractions containing the desired product, concentrating under reduced pressure to obtain compound 183 (2- [ (2-)) as an off-white solidR) -amino [1- (5-amino-1, 2, 4-oxadiazol-3-yl) piperidin-4-yl]Methyl radical]-4, 5-dichlorophenol) (9.8 mg, 16% of two steps in total): C₁₄H₁₇C_l2N₅O₂ [M + H]⁺Calculated lcms (esi): 358, 360 (3: 2), found 358, 360 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 6.87 (s, 1H), 3.90 (d, J = 7.7 Hz, 2H), 3.82 (d, J = 13.1 Hz, 1H), 2.90-2.78 (m, 1H), 2.75 (td, J = 12.6, 3.0 Hz, 1H), 1.94 (d, J = 12.5 Hz, 2H), 1.45-1.20 (m, 3H)。

example 183 Compound 188 (, ( R)-1-(4-((R) -amino (2,3, 4-trichloro-6-hydroxyphenyl) methyl) piperidin-1-yl) -2, 3-dihydroxypropan-1-one trifluoroacetic acid

A, step a:

to a stirred mixture of 2-bromo-3, 4, 5-trichloro-1- (prop-2-en-1-yloxy) benzene (intermediate 9, example 9) (0.35 g, 1.11 mmol) in THF (10 mL) at-65 deg.C under a nitrogen atmosphere was added dropwisenBuLi (0.26 mL of 1.65 mmol, 2.50M in hexane). Stirring at-65 deg.C for 0.5 hr, and adding 4- ([), (II) for 10 min at-65 deg.CS) -2-methylpropan-2-sulfinyl]Imino radical]Methyl) piperidine-1-carboxylic acid tert-butyl ester (0.53 g, 1.66 mmol) in THF (5 mL). The reaction mixture was stirred at-65 ℃ for an additional 0.5 h. The resulting mixture was quenched with water (50 mL) at-65 ℃ and extracted with EA (2X 50 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography, eluting with PE/EA (5:1) to obtain 4- [ (5) [) (R) - [ (2-methylpropane-2-sulfinyl) amino][2,3, 4-trichloro-6- (prop-2-en-1-yloxy) phenyl]Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester (0.25 g, 37%): C₂₄H₃₅Cl₃N₂O₄S [M + H]⁺Calculated lcms (esi): 553, 555, 557 (3: 3: 1), found 553, 555, 557 (3: 3: 1); ¹H NMR (400 MHz, CDCl₃) δ 6.98 (s, 1H), 6.12-5.95 (m, 1H), 5.47-5.40 (m, 2H), 4.76 (t, J = 9.5 Hz, 1H), 4.65-4.56 (m, 2H), 4.48-4.41 (d, J = 10.1 Hz, 1H), 4.26-4.01 (m, 2H), 2.76-2.46 (m, 3H), 2.35 (d, J = 13.7 Hz, 1H), 1.40-1.12 (m, 3H), 1.47 (s, 9H), 1.05 (s, 9H)。

Step b:

4- [ (ii) to stirring at room temperatureR) - [ (2-methylpropane-2-sulfinyl) amino][2,3, 4-trichloro-6- (prop-2-en-1-yloxy) phenyl]Methyl radical]To a solution of tert-butyl piperidine-1-carboxylate (0.25 g, 0.45 mmol) in DCM (2 mL) was added TFA (1 mL) dropwise. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was saturated with NaHCO at 0 deg.C₃The aqueous solution was neutralized to pH 7 and then extracted with EA (5X 50 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography with a solution having 10 mmol/L NH₄HCO₃Is eluted with 40% aqueous ACN to give (a) as a yellow oilS)-N-((R) - (6- (allyloxy) -2,3, 4-trichlorophenyl) (piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (0.14 g, 62%): C₁₉H₂₇Cl₃N₂O₂S [M + H]⁺Calculated lcms (esi): 453, 455, 457 (3: 3: 1), found 453, 455, 457 (3: 3: 1);¹H NMR (400 MHz, CDCl₃) δ 7.03 (s, 1H), 6.14-6.04 (m, 1H), 5.48-5.39 (m, 2H), 5.18-4.99 (m, 1H), 4.82 (d, J = 9.6 Hz, 1H), 4.74-4.55 (m, 2H), 3.59 (d, J = 12.8 Hz, 1H), 3.42 (d, J = 12.7 Hz, 1H), 3.03-2.79 (m, 2H), 2.55-2.44 (m, 1H), 2.36-2.19 (m, 1H), 1.72-1.41 (m, 3H), 1.09 (s, 9H)。

step c:

to stirred HATU (0.20 g, 0.53 mmol) and (4) at room temperatureR) (2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid (77 mg, 0.53 mmol) in DMF (3 mL) was addedS)-N-((R) - (6- (allyloxy) -2,3, 4-trichlorophenyl) (piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (0.12 g, 0.26 mmol) and Et ₃N (54 mg, 0.53 mmol). After stirring at room temperature for 2 hours, the resulting solution was quenched with water (30 mL) at room temperature and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purifying the residue by reverse phase chromatography with a column chromatography column containing20 mmol/L NH₄HCO₃Is eluted with 70% aqueous ACN to give (a) as a yellow oilS)-N-((R) - (6- (allyloxy) -2,3, 4-trichlorophenyl) (1- ((3)R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (44 mg, 28%): C₂₅H₃₅Cl₃N₂O₅S [M + H]⁺Calculated lcms (esi): 581, 583, 585 (3: 3: 1), found 581, 583, 585 (3: 3: 1);¹H NMR (400 MHz, CDCl₃) δ 7.03 (s, 1H), 6.14-5.93 (m, 1H), 5.54-5.32 (m, 2H), 4.83-4.34 (m, 4H), 3.97-3.48 (m, 4H), 3.18-2.90 (m, 2H), 2.70-2.49 (m, 2H), 2.30-2.16 (m, 1H), 1.50-1.20 (m, 9H), 1.03 (s, 9H)。

step d:

stirring under nitrogen atmosphere at room temperatureS)-N-((R) - (6- (allyloxy) -2,3, 4-trichlorophenyl) (1- ((3)R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (40 mg, 0.07 mmol) and Pd (PPh)₃)₄(9 mg, 0.007 mmol) in THF (3 mL) was added NaBH₄(6 mg, 0.15 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The resulting mixture was washed with saturated NH at room temperature₄Aqueous Cl (0.5 mL) was quenched and concentrated under reduced pressure to give crude (A) S)-N-((R)-(1-((R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl) piperidin-4-yl) (2,3, 4-trichloro-6-hydroxyphenyl) methyl) -2-methylpropane-2-sulfinamide. The crude product was used without further purification in the subsequent step: c₂₂H₃₁Cl₃N₂O₅S [M + H]⁺Calculated lcms (esi): 541, 543 (1: 1), measured value 541, 543 (1: 1).

Step e:

at room temperature will: (S)-N-((R)-(1-((R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl) piperidin-4-yl) (2,3, 4-trichloro-6-hydroxyphenyl) methyl) -2-methylpropane-2-sulfinamide (crude) solution in 1, 4-dioxane (5 mL) was added aqueous HCl (6 mL)N, 3 mL). The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column, 5 μm, 19X 150 mm; mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 15% B to 23% B in 7 minutes; a detector: UV 220/254 nm; retention time: 6.5 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 188 as an off-white solid (, (R-F.) (R.) (II)R)-1-(4-((R) -amino (2,3, 4-trichloro-6-hydroxyphenyl) methyl) piperidin-1-yl) -2, 3-dihydroxypropan-1-one trifluoroacetic acid (11.9 mg, 30% of two steps in total) C ₁₅H₁₉Cl₃N₂O₄ [M + H]⁺Lcms (esi) calculated value of (a): 397, 399, 401 (3: 3: 1), found 397, 399, 401 (3: 3: 1);¹H NMR (400 MHz, CD₃OD) δ 7.13 (s, 1H), 4.73-4.49 (m, 3H), 4.18 (dd, J = 65.2, 13.9 Hz, 1H), 3.79-3.50 (m, 2H), 3.20-2.91 (m, 1H), 2.75-2.48 (m, 2H), 2.17-2.00 (m, 1H), 1.54-1.27 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -76.95。

EXAMPLE 184 Compound 189 ((2)R)-1-[4-[(R) -amino (3-hydroxynaphthalen-2-yl) methyl]Piperidin-1-yl]-2, 3-dihydroxypropan-1-one trifluoroacetic acid)

Step a:

to a stirred solution of 2-bromo-3-methoxynaphthalene (0.30 g, 1.3 mmol) in THF (5 mL) was added dropwise under a nitrogen atmosphere at-78 deg.CnBuLi (0.61 mL, 1.5 mmol, 2.5M in hexane). The reaction mixture was stirred at-78 ℃ for 30 minutes under nitrogen atmosphere. 4- ([ ((II) is added dropwise to the above mixture over 5 minutes at-78 DEG CS) -2-methylpropan-2-sulfinyl]Imino radical]Methyl) piperidine-1-carboxylic acid tert-butyl ester (0.30 g, 1 mmol) in THF (2 mL). The resulting mixture was stirred from-78 ℃ to room temperature for an additional 2 hours. The resulting solution was treated with saturated NH at room temperature₄Aqueous Cl (30 mL) and extracted with EA (3X 50 mL)And (6) taking. The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 60% aqueous ACN (plus 0.05% TFA) to give 4- [ ((r)) as an off-white solidR) - (3-methoxynaphthalen-2-yl) ([ ((ii) ()S) -2-methylpropan-2-sulfinyl ]Amino group]) Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester (0.50 g, 83%): C₂₆H₃₈N₂O₄S [M + H]⁺Calculated lcms (esi): 475, measured value 475;¹H NMR (400 MHz, CDCl₃) δ 7.75 (d, J = 8.3 Hz, 2H), 7.55 (s, 1H), 7.49-7.43 (m, 1H), 7.40-7.34 (m, 1H), 7.17 (s, 1H), 4.25-4.12 (m, 2H), 4.08-3.95 (m, 4H), 3.18-3.07 (m, 1H), 2.77-2.49 (m, 2H), 2.20-1.98 (m, 1H), 1.83-1.59 (m, 1H), 1.51-1.28 (m, 11H), 1.26 (s, 9H)。

step b:

4- [ (ii) to stirring at room temperatureR) - (3-methoxynaphthalen-2-yl) ([ ((ii) ()S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]To a solution of tert-butyl piperidine-1-carboxylate (0.30 g, 0.60 mmol) in DCM (2 mL) was added TFA (0.5 mL). The reaction solution was stirred at room temperature for 30 minutes. The mixture was washed with saturated NaHCO at 0 deg.C₃The aqueous solution was basified to pH 8 and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to obtain (A) as a pale yellow oilS)-N-[(R) - (3-methoxynaphthalen-2-yl) (piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.25 g, crude), which was used in the next step without further purification: c₂₁H₃₀N₂O₂S [M + H]⁺Calculated lcms (esi): 375, found 375.

Step c:

stirring at room temperature (4)R) (2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid (0.15 g, 1.00 mmol) and HATU (0.51 g, 1.30 mmol) in DMF (3 mL) was addedS)-N-[(R) - (3-methoxynaphthalen-2-yl) (piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.25 g, 0.70 mmol) and Et₃N (0.20 g, 2.00 mmol). The reaction solution was stirred at room temperature for 30 minutes. The resulting solution was quenched with water (30 mL) and extracted with EA (2X 30 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 60% aqueous ACN (plus 0.05% TFA) and obtained as a pale yellow solid (S)-N-[(R)-[1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical](3-Methoxynaphthalen-2-yl) methyl]2-methylpropane-2-sulfinamide (0.13 g, 38%): C₂₇H₃₈N₂O₅S [M + H]⁺Calculated lcms (esi): 503, found 503;¹H NMR (400 MHz,CDCl₃) δ 7.76 (d, J = 8.0 Hz, 2H), 7.60-7.44 (m, 2H), 7.40 (t, J = 7.5 Hz, 1H), 7.19 (s, 1H), 4.76-4.61 (m, 1H), 4.53-4.28 (m, 2H), 4.26-4.04 (m, 2H), 4.00 (s, 3H), 3.95-3.48 (m, 1H), 3.19-2.82 (m, 1H), 2.69-2.44 (m, 1H), 2.40-2.12 (m, 2H), 1.45-1.23 (m, 9H), 1.12 (d, J = 13.4 Hz, 9H)。

step d:

stirring at room temperature (S)-N-[(R)-[1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical](3-Methoxynaphthalen-2-yl) methyl]To a mixture of (E) -2-methylpropane-2-sulfinamide (0.16 g, 0.30 mmol) in DCM (3 mL) was added BBr₃(0.39 g, 1.6 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched with water (3 mL) at 0 ℃. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column, 5 μm, 19X 150 mm; mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 8% B to 25% B in 7 minutes; a detector: UV 254/220 nm; retention time: 5.38 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure, and yielded compound 189 ((2) as a pale yellow solid R)-1-[4-[(R) -amino (3-hydroxynaphthalen-2-yl) methyl]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid) (29 mg, 21%): C₁₉H₂₄N₂O₄ [M + H]⁺Calculated lcms (esi): 345, found 345;¹H NMR (400 MHz, CD₃OD) δ 7.82-7.75 (m, 2H), 7.69 (d, J = 8.2 Hz, 1H), 7.49-7.42 (m, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.26 (s, 1H), 4.72-4.43 (m, 2H), 4.35-3.96 (m, 2H), 3.77-3.56 (m, 2H), 3.09 (dt, J = 60.5, 13.3 Hz, 1H), 2.82-2.49 (m, 2H), 2.10 (d, J = 12.6 Hz, 1H), 1.54-1.06 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.02。

example 185. Compound 190 ((2)R)-1-[4-[(R) -amino (5-chloro-2-hydroxy-4-methylphenyl) methyl]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid)

Step a:

stirring at room temperature (4)R) (2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid (38 mg, 0.26 mmol) and HATU (0.10 g, 0.26 mmol) in DMF (1 mL) was addedS)-N-[(R) - [ 5-chloro-4-methyl-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]-solution of 2-methylpropane-2-sulfinamide (70 mg, 0.18 mmol) in DMF (1 mL) and Et₃N (35 mg, 0.35 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was quenched with water (40 mL) at room temperature and extracted with EA (3X 20 mL). The combined organic layers were washed with brine (3X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to obtain (A) as a pale yellow oilS)-N-((R) - (2- (allyloxy) -5-chloro-4-methylphenyl) (1- ((2-allyloxy) methylR) 2, 2-dimethyl-1, 3-dioxolane-4-carbonyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (0.12 g, crude): C ₂₆H₃₉ClN₂O₅S [M + H]⁺Lcms (esi) calculated value of (a): 527, 529 (3: 1), found 527, 529 (3: 1).

Step b:

under nitrogen atmosphere, at room temperatureStirring (A)S)-N-((R) - (2- (allyloxy) -5-chloro-4-methylphenyl) (1- ((2-allyloxy) methylR) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (0.12 g, 0.23 mmol) and Pd (PPh)₃)₄(52 mg, 0.05 mmol) in THF (2 mL) NaBH was added₄(17 mg, 0.46 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The resulting mixture was quenched with water (3 mL) and concentrated under reduced pressure to give (A) as a brown oilS)-N-[(R) - (5-chloro-2-hydroxy-4-methylphenyl) ([1- [ (4)R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]2-methylpropane-2-sulfinamide (0.12 g, crude), which was used in the subsequent step without further purification C₂₃H₃₅ClN₂O₅S [M + H]⁺Calculated lcms (esi): 487, 489 (3: 1), found 487, 489 (3: 1).

Step c:

stirring at room temperature (S)-N-[(R) - (5-chloro-2-hydroxy-4-methylphenyl) ([1- [ (4)R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide (0.12 g, crude) in THF (2 mL) aqueous HCl (4) was added N1 mL). The resulting mixture was stirred at room temperature for an additional 30 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column X Bridge Shield RP18 OBD column, 5 μm, 19X 150 mm; mobile phase a: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 10% B to 20% B in 7 minutes; detector UV 220 nm; retention time: 5.62 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure to give compound 190 ((2) as an off-white solidR)-1-[4-[(R) -amino (5-chloro-2-hydroxy-4-methylphenyl) methyl]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid) (27 mg, 22% of a three-step total): C₁₆H₂₃ClN₂O₄ [M + H]⁺Calculated lcms (esi): 343, 345 (3: 1), found 343, 345 (3: 1); ¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 6.85 (s, 1H), 4.73-4.38 (m, 2H), 4.37-3.90 (m, 2H), 3.87-3.47 (m, 2H), 3.22-2.93 (m, 1H), 2.66 (dt, J = 45.2, 12.9 Hz, 1H), 2.38 (s, 1H), 2.32 (s, 3H), 2.02 (s, 1H), 1.51-1.08 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.08.

in a manner analogous to that described for compound 190, fromS)-N-[(R) - [ 5-chloro-4-methyl-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]Starting with 2-methylpropane-2-sulfinamide and the corresponding acid (which is prepared as described herein, or is available from a commercial source), the compounds in table 1c below are prepared.

TABLE 1c

EXAMPLE 186 Compound 191 ((2)R)-1-[4-[(R) -amino (2-hydroxynaphthalen-1-yl) methyl]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid)

A, step a:

1-bromo-2-methoxynaphthalene stirred at-78 ℃ under nitrogen(0.35 g, 1.50 mmol) in THF (5 mL) was added dropwisenBuLi (0.71 mL, 1.80 mmol, 2.5M in hexane). The resulting solution was stirred at-78 ℃ for 30 minutes under nitrogen. 4- ([ ((II) is added dropwise to the above solution at-78 ℃ over 5 minutesS) -2-methylpropan-2-sulfinyl]Imino radical]Methyl) piperidine-1-carboxylic acid tert-butyl ester (0.35 g, 1.10 mmol) in THF (2 mL). The resulting solution was warmed to room temperature and stirred for an additional 2 hours. The reaction was quenched with saturated NH at room temperature₄Aqueous Cl (20 mL) was quenched. The resulting mixture was extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE/EA (1/1) to give 4- [ (R) in the form of a pale yellow oilR) - (2-methoxynaphthalen-1-yl) ([ ((ii) ((iii))S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester (0.30 g, 34%): C₂₆H₃₈N₂O₄S [M + H]⁺Calculated lcms (esi): 475, measured value 475;¹H NMR (400 MHz,CDCl₃) δ 7.97 (d, J = 8.7 Hz, 1H), 7.84-7.79 (m, 2H), 7.56-7.48 (m, 1H), 7.42-7.35 (m, 1H), 7.32 (d, J = 9.2 Hz, 1H), 5.01 (d, J = 10.0 Hz, 1H), 4.30-4.16 (m, 1H), 4.05-3.89 (m, 4H), 2.78-2.63 (m, 1H), 2.52-2.36 (m, 2H), 2.27-2.15 (m, 1H), 1.45 (d, J = 3.9 Hz, 12H), 0.97 (s, 9H)。

step b:

4- [ (ii) to stirring at room temperatureR) - (2-methoxynaphthalen-1-yl) ([ ((ii) ((iii))S) -2-methylpropan-2-sulfinyl ]Amino group]) Methyl radical]To a solution of tert-butyl piperidine-1-carboxylate (0.20 g, 0.42 mmol) in DCM (4 mL) was added TFA (1 mL). The resulting solution was stirred at room temperature for 30 minutes. The mixture was washed with saturated NaHCO at 0 deg.C₃The aqueous solution was basified to pH 8. The resulting mixture was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to obtain (A) as a pale yellow oilS)-N-[(R) - (2-methoxynaphthalen-1-yl) (piperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide(0.2 g, crude), which was used in the next step without further purification: c₂₁H₃₀N₂O₂S [M + H]⁺Calculated lcms (esi): 375, found 375;¹H NMR (400 MHz, CD₃OD) δ 8.12-8.04 (m, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.89-7.82 (m, 1H), 7.60-7.53 (m, 1H), 7.53-7.46 (m, 1H), 7.44-7.36 (m, 1H), 5.01 (d, J = 9.7 Hz, 1H), 4.07 (s, 3H), 3.55 (d, J = 13.3 Hz, 1H), 3.23 (d, J = 12.7 Hz, 1H), 3.09-2.98 (m, 1H), 2.88-2.73 (m, 1H), 2.69-2.58 (m, 1H), 2.56-2.29 (m, 1H), 1.70-1.56 (m, 1H), 1.50-1.26 (m, 2H), 0.98 (s, 9H)。

step c:

stirring at room temperature (4)R) (2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid (78 mg, 0.50 mmol) and HATU (0.30 g, 0.80 mmol) in DMF (2 mL) was addedS)-N-[(R) - (2-methoxynaphthalen-1-yl) (piperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide (0.20 g, 0.50 mmol) and Et₃N (0.16 g, 1.6 mmol). The reaction was stirred at room temperature for 30 minutes. The resulting solution was quenched with water (30 mL) and extracted with EA (2X 30 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 57% aqueous ACN (plus 0.05% TFA) to give (a) as a pale yellow oilS)-N-[(R)-[1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical](2-Methoxynaphthalen-1-yl) methyl]2-methylpropane-2-sulfinamide (0.16 g, 47%): C₂₇H₃₈N₂O₅S [M + H]⁺Calculated lcms (esi): 503, found 503;¹H NMR (400 MHz, CDCl₃) δ 7.97-7.90 (m, 1H), 7.90-7.80 (m, 3H), 7.59-7.49 (m, 1H), 7.44-7.30 (m, 1H), 4.98-4.83 (m, 1H), 4.82-4.46 (m, 2H), 4.45-4.29 (m, 1H), 4.29-4.19 (m, 1H), 4.10-4.02 (m, 3H), 4.02-3.90 (m, 1H), 3.89-3.49 (m, 1H), 3.20-2.98 (m, 1H), 2.68-2.29 (m, 2H), 1.60-1.22 (m, 9H), 1.01 (d, J = 3.6 Hz, 9H)。

step d:

stirring at room temperature (S)-N-[(R)-[1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical](2-Methoxynaphthalen-1-yl) methyl]To a mixture of (E) -2-methylpropane-2-sulfinamide (0.16 g, 0.31 mmol) in DCM (3 mL) was added BBr₃(0.18 g, 1.90 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched with water (5 mL) at 0 ℃. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column, 5 μm, 19X 150 mm; mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 8% B to 25% B in 7 minutes; a detector: UV 254/220 nm; retention time: 4.70 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure, and compound 191 ((2) was obtained as a pale yellow solid R)-1-[4-[(R) -amino (2-hydroxynaphthalen-1-yl) methyl]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid) (38 mg, 25%): C₁₉H₂₄N₂O₄ [M + H]⁺Calculated lcms (esi): 345, found 345;¹H NMR (400 MHz, CD₃OD) δ 8.01 (d, J = 8.4 Hz, 1H), 7.86 (t, J = 7.7 Hz, 2H), 7.56 (t, J = 7.7 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.24 (d, J = 8.9 Hz, 1H), 4.89-4.84 (m, 1H), 4.71 (d, J = 13.5 Hz, 1H), 4.57-4.39 (m, 1H), 4.13 (dd, J = 115.7, 13.8 Hz, 1H), 3.81-3.52 (m, 2H), 3.05 (dt, J = 82.6, 13.2 Hz, 1H), 2.86-2.43 (m, 2H), 2.25-2.07 (m, 1H), 1.67-1.40 (m, 1H), 1.40-1.14 (m, 2H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -76.97.

example 187 Compound 192 (1- [4- [ (()R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidin-1-yl radical]-2- (oxetan-3-yloxy) ethan-1-one)

Step a:

stirring at room temperature to 2Lithium (oxetan-3-yloxy) acetate (0.26 g, 1.85 mmol) and HATU (0.70 g, 1.85 mmol) in DMF (4 mL) was addedN-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]-2,2, 2-trifluoroacetamide (intermediate 38, example 38) (0.38 g, 0.92 mmol) and Et₃N (0.28 g, 2.77 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was purified by reverse phase chromatography eluting with 55% aqueous ACN (plus 0.05% TFA) as a pale yellow solidN-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([1- [2- (oxetan-3-yloxy) acetyl group)]Piperidin-4-yl radical]) Methyl radical]2,2, 2-Trifluoroacetamide (0.20 g, 37% of two-stage sum): C₂₂H₂₅Cl₂F₃N₂O₅ [M + H]⁺Calculated lcms (esi): 525, 527 (3: 2), found 525, 527 (3: 2).

Step b:

at room temperature with stirring N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([1- [2- (oxetan-3-yloxy) acetyl)]Piperidin-4-yl radical]) Methyl radical]-2,2, 2-trifluoroacetamide (0.20 g, 0.38 mmol) and Pd (PPh)₃)₄(4.4 mg, 0.004 mmol) in THF (3 mL) NaBH was added₄(29 mg, 0.76 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated NH at room temperature₄Aqueous Cl (1 mL) was quenched. The resulting mixture was concentrated under reduced pressure to give a brown solidN-[(R) - (4, 5-dichloro-2-hydroxyphenyl) ([1- [2- (oxetan-3-yloxy) acetyl]Piperidin-4-yl radical]) Methyl radical]2,2, 2-trifluoroacetamide (0.20 g, crude), which was used in the next step without further purification: c₁₉H₂₁Cl₂F₃N₂O₅ [M + H]⁺Calculated lcms (esi): 485, 487 (3: 2), measured value 485, 487 (3: 2);

step c:

at room temperature with stirringN-[(R) - (4, 5-dichloro-2-hydroxyphenyl) ([1- [2- (oxetan-3-yloxy) acetyl]Piperidin-4-yl radical]) Methyl radical]-2,2, 2-trifluoroacetamide (0.20 g, 0.41 mmol) in MeOH (2 mL)To the solution in (1), KOH (35 mg, 0.62 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. The mixture was washed with aqueous HCl (1)N) Acidified to pH 7. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column, 5 μm, 19X 150 mm; mobile phase A: has 10 mmoL/L NH ₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 24% B to 30% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.35 minutes. Collecting the fractions containing the desired product, concentrating under reduced pressure to obtain compound 192 (1- [4- [ (1- [)) as an off-white solidR) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidin-1-yl radical]-2- (oxetan-3-yloxy) ethan-1-one) (45 mg, 30% of two steps in total): C₁₇H₂₂Cl₂N₂O₄ [M + H]⁺Calculated lcms (esi): 389, 391 (3: 2), found 389, 391 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.23 (d, J = 2.8 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 4.81-4.70 (m, 2H), 4.70-4.41 (m, 4H), 4.30-4.12 (m, 2H), 3.92-3.72 (m, 2H), 3.10-2.91 (m, 1H), 2.71-2.43 (m, 1H), 2.12-1.92 (m, 2H), 1.48 (d, J = 13.3 Hz, 1H), 1.42-1.05 (m, 2H)。

EXAMPLE 188 Compound 196 ((2)R) -1- [4- [ (4, 5-dichloro-2-hydroxyphenyl) (methylamino) methyl]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid)

Step a:

stirring at room temperature (4)R) To a solution of-2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid (0.61 g, 4.17 mmol) in DMF (10 mL) were added EDCI (1.00 g, 5.22 mmol) and HOBt (0.70 g, 5.18 mmol). To the above mixture was added 4- (4, 5-dichloro-2-methoxybenzoyl) piperidine (example 3, step a) (1.00 g, 3.47 mmol) and Et at room temperature₃N (1.05 g, 10.37 mmol). The reaction mixture was stirred at room temperature for 12 hours. Mixing the reactionCompound H₂Dilution with O (80 mL). The resulting mixture was extracted with EA (3X 40 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with a solution containing 10 mmol/L NH₄HCO₃Was eluted with 30% aqueous ACN to give 4- (4, 5-dichloro-2-methoxybenzoyl) -1- [ (4) as a yellow oilR) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidine (0.68 g, 34%): C₁₉H₂₃Cl₂NO₅ [M + H]⁺Calculated lcms (esi): 416, 418 (3: 2), found 416, 418 (3: 2);

step b:

to stirred 4- (4, 5-dichloro-2-methoxybenzoyl) -1- [ (4) at room temperature under nitrogen atmosphereR) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]To a mixture of piperidine (0.46 g, 1.10 mmol) and methylamine hydrochloride (0.37 g, 5.52 mmol) in THF (20 mL) was added Ti (OEt)₄(1.00 g, 5.52 mmol). The resulting mixture was stirred at 70 ℃ for 12 hours under nitrogen atmosphere. After cooling to room temperature, NaBH was added under nitrogen at room temperature₄(8 mg, 0.22 mmol) was added to the above mixture. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. Reaction with H at room temperature₂O (50 mL) quench. The resulting mixture was extracted with EA (3X 40 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to obtain [ (4, 5-dichloro-2-methoxyphenyl) ([1- [ (4) ] as a yellow solid R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl]) Methyl radical](methyl) amine (0.39 g, crude): C₂₀H₂₈Cl₂N₂O₄ [M + H]⁺Calculated lcms (esi): 431 and 433 (3: 2), found 431 and 433 (3: 2).

Step c:

stirring to 0 deg.C [ (4, 5-dichloro-2-methoxyphenyl) ([1- [ (4) ]R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical](methyl) amine (0.39 g, 0.90 mmol) in DCM (4 mL) was added dropwiseAdding BBr₃(1 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with MeOH (2 mL). The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column 19X 150 mm, 5 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 5% B to 30% B in 7 minutes; a detector: UV 254/220 nm; retention time: 5.92 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 196 ((2) as an off-white solidR) -1- [4- [ (4, 5-dichloro-2-hydroxyphenyl) (methylamino) methyl]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid) (0.14 g, 30%): C₁₆H₂₂Cl₂N₂O₄ [M + H]⁺Calculated lcms (esi): 377, 379 (3: 2), found 377, 379 (3: 2); ¹H NMR (400 MHz, CD₃OD) δ 7.44 (s, 1H), 7.11 (s, 1H), 4.71-4.31 (m, 2H), 4.31-4.03 (m, 2H), 3.85-3.51 (m, 2H), 3.25-2.98 (m, 1H), 2.84-2.36 (m, 5H), 2.05 (s, 1H), 1.54-1.01 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.19.

Example 189 Compound 193 ((2)R) -1- [4- [ (4, 5-dichloro-2-hydroxyphenyl) (dimethylamino) methyl group]Piperidin-1-yl]-2, 3-dihydroxypropan-1-one trifluoroacetic acid)

Step a:

stirring at room temperature (2)R) -1- [4- [ (4, 5-dichloro-2-hydroxyphenyl) (methylamino) methyl]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one (free base of Compound 196, example 188) (50 mg, 0.13 mmol), HOAc (35 mg, 0.42 mmol) and HCHO (6 mg, 0.22 mmol) in MeOH (1 mL) were added NaBH in portions₃CN (27 mg, 0.42 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 hours. The resulting mixture was quenched with water (5 mL) at room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Prep C18 OBD column 19X 150 mm, 5 μm; mobile phase A:water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 5% B to 30% B in 7 minutes; a detector: UV 254/220 nm; retention time: 5.85 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure to give compound 193 ((2) as an off-white solidR) -1- [4- [ (4, 5-dichloro-2-hydroxyphenyl) (dimethylamino) methyl group]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid) (29 mg, 43%): C ₁₇H₂₄Cl₂N₂O₄ [M + H]⁺Calculated lcms (esi): 391, 393 (3: 2), found 391, 393 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.56 (s, 1H), 7.15 (s, 1H), 4.82-4.36 (m, 3H), 4.33-4.06 (m, 1H), 3.78-3.53 (m, 2H), 3.28-3.03 (m, 1H), 2.98-2.60 (m, 8H), 2.11-1.80 (m, 1H), 1.54 (s, 1H), 1.40-1.01 (m, 2H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -76.67.

EXAMPLE 190 Compound 198 ((2)R)-1-[4-[(R) -amino (4-chloro-2-hydroxy-5-methylphenyl) methyl]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one)

Step a:

stirred at room temperature under nitrogen atmosphere (4)R) To a solution of-2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid (50 mg, 0.34 mmol) and HATU (151 mg, 0.40 mmol) in DMF (2 mL) was added Et₃N (53 mg, 0.53 mmol) and N- [ (II) ((III))R) - [ 4-chloro-5-methyl-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]2, 2-Dimethylpropanamide (0.10 g, 0.26 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 12 hours. The reaction was quenched with water (20 mL) and extracted with EA (3X 10 mL). The combined organic layers were washed with brine (3X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. Filtering, concentrating the filtrate under reduced pressure to obtain light yellow oilN-[(R) - [ 4-chloro-5-methyl-2- (prop-2-en-1-yloxy) phenyl]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]-2, 2-dimethylPropionamide (180 mg, crude): C₂₆H₃₉ClN₂O₅S [M + H]⁺Calculated lcms (esi): 527, 529 (3: 1), found 527, 529 (3: 1).

Step b:

under nitrogen atmosphere, to stirring N-[(R) - [ 4-chloro-5-methyl-2- (prop-2-en-1-yloxy) phenyl]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]-2, 2-Dimethylpropionamide (180 mg, crude) and Pd (PPh)₃)₄(15 mg, 0.01 mmol) in THF (5 mL) was added NaBH three times₄(27 mg, 0.71 mmol). The resulting solution was stirred at room temperature under nitrogen for 1 hour. The resulting mixture was quenched with water (3 mL) and concentrated under reduced pressure to give (A) as a brown oilS)-N-((R) - (4-chloro-2-hydroxy-5-methylphenyl) (1- ((2-hydroxy-5-methyl-phenyl)R) 2, 2-dimethyl-1, 3-dioxolane-4-carbonyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (0.12 g, crude), which was used in the subsequent step without further purification C₂₆H₃₉ClN₂O₅S [M + H]⁺Calculated lcms (esi): 527, 529 (3: 1), found 527, 529 (3: 1).

Step c:

stirring at room temperature (S)-N-((R) - (4-chloro-2-hydroxy-5-methylphenyl) (1- ((2-hydroxy-5-methyl-phenyl)R) (ii) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (0.12 g, crude) in THF (2 mL) was added aqueous HCl (4. mu.g)N1 mL). The resulting mixture was stirred at room temperature for an additional 30 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column, 5 μm, 19X 150 mm; mobile phase A: having a NH concentration of 10 mmol/L ₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 11% B to 26% B in 9 minutes; a detector: UV 220 nm; retention time: 6.1 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure to afford compound 198 ((2) as an off-white solidR)-1-[4-[(R) -amino (4-chloro-2-hydroxy-5-methylphenyl) methylBase of]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one) (26.1 mg, 31% of three steps in total): C₁₆H₂₃ClN₂O₄ [M + H]⁺Calculated lcms (esi): 343, 345 (3: 1), found 343, 345 (3: 1);¹H NMR (400 MHz, CD₃OD) δ 6.98 (s, 1H), 6.76 (s, 1H), 4.67-4.40 (m, 2H), 4.10 (dd, J = 48.1, 13.7 Hz, 1H), 3.85 (dd, J = 7.9, 3.6 Hz, 1H), 3.76-3.53 (m, 2H), 3.10-2.96 (m, 1H), 2.73-2.50 (m, 1H), 2.25 (s, 3H), 2.02 (s, 2H), 1.53-1.40 (m, 1H), 1.33-1.14 (m, 2H)。

EXAMPLE 191 Compound 201 (1- [4- [ (()R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidin-1-yl radical]-2, 3-dihydroxy-2-methylpropan-1-one trifluoroacetic acid)

Step a:

to a stirred solution of 2-methylprop-2-enoic acid (92 mg, 1.07 mmol) and HATU (0.41 g, 1.07 mmol) in DMF (3 mL) at room temperature was added (bS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.30 g, 0.72 mmol) and Et₃N (0.14 g, 1.43 mmol). The reaction solution was stirred at room temperature for 1 hour. The resulting solution was quenched with water (40 mL) and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 55% aqueous ACN (plus 0.05% TFA) and obtained as an off-white semisolid (f S)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (2-methylprop-2-enoyl) piperidin-4-yl]Methyl radical]2-methylpropane-2-sulfinamide (0.30 g, 86%): C₂₃H₃₂Cl₂N₂O₃S [M + H]⁺Calculated lcms (esi): 487, 489 (3: 2), found 487, 489 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.29 (s, 1H), 6.99 (s, 1H), 6.11-5.97 (m, 1H), 5.48-5.32 (m, 2H), 5.21 (s, 1H), 5.05 (s, 1H), 4.72-4.24 (m, 3H), 4.18-3.92 (m, 1H), 3.10-2.87 (m, 1H), 2.72-2.49 (m, 1H), 2.26-2.01 (m, 3H), 1.95 (s, 3H), 1.52-1.39 (m, 3H), 1.25-1.12 (m, 9H)。

step b:

stirring under nitrogen atmosphere at room temperatureS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (2-methylprop-2-enoyl) piperidin-4-yl group]Methyl radical]-2-methylpropane-2-sulfinamide (0.30 g, 0.62 mmol) and Pd (PPh)₃)₄ (7 mg, 0.01 mmol) in THF (2 mL) NaBH was added₄(47 mg, 1.23 mmol). The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was reacted with saturated NH at room temperature₄Aqueous Cl (1 mL) was quenched and concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 60% aqueous ACN (plus 0.05% TFA) and afforded as a brown solid (S)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) [1- (2-methylprop-2-enoyl) piperidin-4-yl]Methyl radical]2-methylpropane-2-sulfinamide (0.24 g, 87%): C₂₀H₂₈Cl₂N₂O₃S [M + H]⁺Calculated lcms (esi): 447, 449 (3: 2), found 447, 449 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.36 (s, 1H), 6.95 (s, 1H), 5.22 (s, 1H), 5.04 (s, 1H), 4.64-4.28 (m, 2H), 4.16-3.88 (m, 2H), 3.18-2.95 (m, 1H), 2.78-2.58 (m, 1H), 2.21 (d, J = 13.7 Hz, 1H), 2.15-2.06 (m, 1H), 1.94 (s, 3H), 1.41 (d, J = 13.4 Hz, 1H), 1.33-1.19 (m, 1H), 1.14 (s, 9H)。

step c:

stirring at room temperature (S)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) [1- (2-methylprop-2-enoyl) piperidin-4-yl ]Methyl radical](iii) -2-methylpropane-2-sulfinamide (0.20 g, 0.45 mmol) in 1, 4-dioxane (2 mL) to which was added aqueous HCl (4)N2 mL). The reaction was stirred at room temperature for 1 hour. Concentrating the reaction solution under reduced pressure to obtain 1- [4- [ (R) ((R)) in the form of light yellow oilR) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidin-1-yl radical]-2-methylprop-2-en-1-one (0.15 g, crude), without further purificationThe chemistry was used directly in the next step: c₁₆H₂₀Cl₂N₂O₂[M + H]⁺Calculated lcms (esi): 343, 345 (3: 2), found 343, 345 (3: 2); ¹H NMR (400 MHz, CD₃OD) δ 7.46 (s, 1H), 7.09 (s, 1H), 5.25 (s, 1H), 5.07 (s, 1H), 4.72-4.40 (m, 1H), 4.23-3.94 (m, 2H), 3.25-2.98 (m, 1H), 2.88-2.52 (m, 1H), 2.47-2.34 (m, 1H), 2.11-1.97 (m, 1H), 1.95 (s, 3H), 1.47-1.28 (m, 3H)。

step d:

stirring at room temperature (S)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) [1- (2-methylprop-2-enoyl) piperidin-4-yl]Methyl radical]-2-methylpropane-2-sulfinamide (0.15 g, 0.34 mmol) and citric acid (48 mg, 0.25 mmol) intAddition of K to a mixture of BuOH (1 mL) and Water (1 mL)₂OsO₂(OH)₄ (31 mg, 0.08 mmol) and NMO (47 mg, 0.40 mmol). The reaction mixture was stirred at room temperature for 1 hour. The resulting solution was purified by reverse phase chromatography eluting with 20% aqueous ACN (plus 0.05% TFA). The fractions containing the desired product were concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column, 5 μm, 19X 150 mm; mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 12% B to 23% B in 7 minutes; a detector: UV 254/220 nm; retention time 6.38 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 201 (1- [4- [ (1- [)) as an off-white solid R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidin-1-yl]-2, 3-dihydroxy-2-methylpropan-1-one trifluoroacetic acid) (55 mg, 25% of the total of the two steps) C₁₆H₂₂Cl₂N₂O₄ [M + H]⁺Calculated lcms (esi): 377, 379 (3: 2), found 377, 379 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.43 (s, 1H), 7.08 (s, 1H), 4.75-4.50 (m, 2H), 4.15 (d, J = 9.6 Hz, 1H), 3.72 (d, J = 11.2 Hz, 1H), 3.56 (d, J = 11.2 Hz, 1H), 3.07-2.54 (m, 2H), 2.49-2.31 (m, 1H), 2.11-1.91 (m, 1H), 1.51-1.09 (m, 6H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.02.

example 192. Compound 202 ((2)R) -1- [4- [ (4, 5-dichloro-2-hydroxyphenyl) (ethylamino) methyl]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid)

Step a:

to a stirred mixture of 4- (4, 5-dichloro-2-methoxybenzoyl) -1- [ (4) at room temperatureR) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]To a mixture of piperidine (example 188, step a) (0.22 g, 0.53 mmol) and ethylamine hydrochloride (0.22 g, 2.64 mmol) in THF (10 mL) was added Ti (OEt)₄(0.60 g, 2.64 mmol). The reaction mixture was stirred at 70 ℃ for 12 hours under nitrogen atmosphere. After cooling to room temperature, the NaBH is cooled at room temperature₄(34 mg, 0.11 mmol) was added to the above mixture. The reaction mixture was stirred at room temperature for 1 hour. Reaction with H at room temperature₂O (40 mL) quench. The resulting mixture was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to obtain [ (4, 5-dichloro-2-methoxyphenyl) ([1- [ (4) ] as a yellow solid R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl]) Methyl radical](Ethyl) amine (0.23 g, crude): C₂₁H₃₀Cl₂N₂O₄ [M + H]⁺Calculated lcms (esi): 445, 447 (3: 2), found 445, 447 (3: 2).

Step b:

stirring to 0 deg.C [ (4, 5-dichloro-2-methoxyphenyl) ([1- [ (4) ]R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical](Ethyl) amine (0.23 g, 0.52 mmol) in DCM (2 mL) was added BBr dropwise₃(0.5 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with MeOH (2 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column 19X 150 mm, 5 μm; mobile phase A of water (add)0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 10% B to 30% B in 7 minutes; a detector: UV 254/220 nm; retention time: 5.57 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 202 ((2) as an off-white solidR) -1- [4- [ (4, 5-dichloro-2-hydroxyphenyl) (ethylamino) methyl]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid) (56 mg, 21%): C₁₇H₂₄Cl₂N₂O₄ [M + H]⁺Calculated lcms (esi): 391, 393 (3: 2), found 391, 393 (3: 2); ¹H NMR (400 MHz, CD₃OD) δ 7.45 (s, 1H), 7.11 (s, 1H), 4.73-4.42 (m, 2H), 4.31-4.02 (m, 2H), 3.66 (d, J = 19.9 Hz, 2H), 3.08 (dt, J = 45.1, 12.8 Hz, 1H), 2.98-2.80 (m, 2H), 2.66 (dt, J = 44.7, 12.8 Hz, 1H), 2.56-2.23 (m, 1H), 2.18-1.95 (m, 1H), 1.54-1.07 (m, 6H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.24.

Example 193 Compound 212 ((2)R)-1-[(1R,5S,6R) -6- [ amino- (4, 5-dichloro-2-hydroxyphenyl) methyl group]-3-azabicyclo [ 2 ]3.1.0]Hexane-3-yl]-2, 3-dihydroxypropan-1-one)

Step a:

to a stirred solution of 1-bromo-4, 5-dichloro-2- (prop-2-en-1-yloxy) benzene (example 6, step b) (1.12 g, 4.14 mmol) in THF (5 mL) at-10 deg.C under a nitrogen atmosphere was added dropwisei-PrMgCl. LiCl (3.98 mL, 5.18 mmol, 1.3M THF solution). The reaction was stirred at 0 ℃ for 30 minutes. Then added dropwise at-10 ℃ over 0.5 hour (1)R,5S,6R) -6- [ methoxy (methyl) carbamoyl]-3-azabicyclo [ 2 ]3.1.0]Hexane-3-carboxylic acid tert-butyl ester (0.28 g, 1.04 mmol) in THF (2 mL). The reaction was stirred at-10 ℃ for 2 hours. Reacting with saturated NH₄Aqueous Cl (30 mL) was quenched and extracted with EA (3X 20 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄Drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE/EA (5/1) to give (1) as a pale yellow oilR,5S,6R) -6- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl]-3-azabicyclo [ 2 ]3.1.0]Hexane-3-carboxylic acid tert-butyl ester (0.19 g, 40%) C₂₀H₂₃Cl₂NO₄ [M + H]⁺Calculated lcms (esi): 412, 414 (3: 2), found 412, 414 (3: 2); ¹H NMR (400 MHz, CDCl₃) δ 7.68 (s, 1H), 7.09 (s, 1H), 6.14-5.96 (m, 1H), 5.56-5.35 (m, 2H), 4.66-4.57 (m, 2H), 3.75-3.54 (m, 3H), 3.54-3.39 (m, 2H), 2.32-2.27 (m, 2H), 1.47 (d, J = 2.6 Hz, 9H)。

Step b:

stirring under nitrogen atmosphere at room temperatureR,5S,6R) -6- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl]-3-azabicyclo [ 2 ]3.1.0]To a solution of tert-butyl hexane-3-carboxylate (0.19 g, 0.46 mmol) and tert-butanesulfinamide (84 mg, 0.69 mmol) in THF (5 mL) was added Ti (OEt)₄(0.42 g, 1.84 mmol). The reaction was stirred at 70 ℃ for 16 hours. After cooling to room temperature, the reaction was quenched with saturated Na₂CO₃Aqueous solution (30 mL) was quenched. The resulting mixture was filtered through celite (celite), and the filtrate was diluted with EA (30 mL) and water (30 mL). The aqueous layer was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give (1) as a yellow oilR,5S,6R) -6- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][ (2-methylpropane-2-sulfinyl) imino]Methyl radical]-3-azabicyclo [ 2 ]3.1.0]Hexane-3-carboxylic acid tert-butyl ester (0.20 g, crude), which was used in the next step without further purification: c₂₄H₃₂Cl₂N₂O₄S[M + H]⁺Calculated lcms (esi): 515, 517 (3: 2), found 515, 517 (3: 2).

Step c:

stirring at room temperature (1)R,5S,6R) -6- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][(2-methylpropane-2-sulfinyl) imino ]Methyl radical]-3-azabicyclo [ 2 ]3.1.0]Hexane-3-carboxylic acid tert-butyl ester (0.20 g, 0.39 mmol) in THF (5 mL) NaBH was added₄(29 mg, 0.78 mmol). The reaction was stirred at room temperature for 1 hour. Reacting with saturated NH₄Aqueous Cl (2 mL) was quenched and diluted with EA (20 mL) and water (30 mL). The aqueous layer was extracted with EA (3X 20 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give (1) as a pale yellow oilR,5S,6R) -6- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]-3-azabicyclo [ 2 ]3.1.0]Hexane-3-carboxylic acid tert-butyl ester (0.18 g, 90%) which was used directly in the subsequent step without further purification C₂₄H₃₄Cl₂N₂O₄S[M + H]⁺Calculated lcms (esi): 517, 519 (3: 2), found 517, 519 (3: 2).

Step d:

stirring at room temperature (1)R,5S,6R) -6- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]-3-azabicyclo [ 2 ]3.1.0]To a solution of tert-butyl hexane-3-carboxylate (0.18 g, 0.35 mmol) in DCM (5 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 0.5 h. The reaction was saturated with Na₂CO₃Aqueous solution (20 mL) was quenched with saturated Na ₂CO₃The aqueous solution (30 mL) was neutralized to pH 7. The resulting solution was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. Filtering, concentrating the filtrate under reduced pressure to obtain yellow oilN-[[(1R,5S,6R) -3-azabicyclo [ 2 ]3.1.0]Hexane-6-yl][4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]2-methylpropane-2-sulfinamide (0.18 g, crude), which was used in the next step without further purification: c₁₉H₂₆Cl₂N₂O₂S [M + H]⁺Calculated lcms (esi): 417, 419, (3: 2), found 417, 419, (3: 2).

Step e:

stirring at room temperature (4R) To a solution of (E) -2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid (0.13 g, 0.86 mmol) and HATU (0.33 g, 0.86 mmol) in DMF (2 mL) was addedN-[[(1R,5S,6R) -3-azabicyclo [ 2 ]3.1.0]Hexane-6-yl][4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]-2-methylpropane-2-sulfinamide (0.18 g, 0.43 mmol) and Et₃N (0.13 g, 1.29 mmol). The reaction was stirred at room temperature for 1 hour. The resulting solution was quenched with water (50 mL) and extracted with EA (3X 40 mL). The combined organic layers were washed with brine (2X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 56% aqueous ACN (plus 0.05% TFA) to afford the product as a yellow oil N- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][(1R,5S,6R)-3-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]-3-azabicyclo [ 2 ]3.1.0]Hexane-6-yl]Methyl radical]2-methylpropane-2-sulfinamide (0.14 g, 56% of the total of the four stages): C₂₅H₃₄Cl₂N₂O₅S [M + H]⁺Calculated lcms (esi): 545, 547, (3: 2), found 545, 547 (3: 2).

Step f:

under nitrogen atmosphere at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][(1R,5S,6R)-3-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]-3-azabicyclo [ 2 ]3.1.0]Hexane-6-yl]Methyl radical]-2-methylpropane-2-sulfinamide (0.14 g, 0.26 mmol) and Pd (PPh)₃)₄ (3 mg, 0.003 mmol) in THF (2 mL) NaBH was added₄ (19 mg, 0.51 mmol). The reaction was stirred at room temperature for 30 minutes under nitrogen atmosphere. Reacting with saturated NH₄Aqueous Cl (1 mL) was quenched and concentrated under reduced pressure to give a brown oilN- [ (4, 5-dichloro-2-hydroxyphenyl) [ (1)R,5S,6R)-3-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]-3-azabicyclo [ 2 ]3.1.0]Hexane-6-yl]Methyl radical]-2-methylpropan-2-ylideneSulfonamide (0.20 g, crude), which was used in the next step without further purification: c₂₂H₃₀Cl₂N₂O₅S [M + H]⁺Calculated lcms (esi): 505, 507 (3: 2), found 505, 507 (3: 2).

Step g:

at room temperature with stirringN- [ (4, 5-dichloro-2-hydroxyphenyl) [ (1)R,5S,6R)-3-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]-3-azabicyclo [ 2 ]3.1.0]Hexane-6-yl]Methyl radical](iii) -2-methylpropane-2-sulfinamide (30 mg, 0.06 mmol) in 1, 4-dioxane (5 mL) to which was added aqueous HCl (4)N2 mL). The reaction was stirred at room temperature for 1 hour. The reaction was performed with EA (20 mL) and HCl (1)N20 mL). The organic layer was washed with aqueous HCl (1)N2X 20 mL). The combined aqueous layers were concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xselect CSH OBD column 30X 150 mm 5 μm; mobile phase A: has 10 mmoL/L NH₄HCO₃Water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 7% B to 20% B in 8 minutes; a detector: UV 254/220 nm; retention time: 6.55 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to afford compound 212 ((2) as an off-white solidR)-1-[(1R,5S,6R) -6- [ amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]-3-azabicyclo [ 2 ]3.1.0]Hexane-3-yl]-2, 3-dihydroxypropan-1-one) (3 mg, 16%): C₁₅H₁₈Cl₂N₂O₄ [M + H – 17]⁺Calculated lcms (esi): 344, 346 (3: 2), found 344, 346 (3: 2);¹H NMR (400 MHz, CD₃OD)δ 7.53-7.40 (m, 1H), 7.08 (s, 1H), 4.40-4.12 (m, 1H), 4.04-3.85 (m, 2H), 3.85-3.58 (m, 3H), 3.56-3.38 (m, 2H), 2.01-1.68 (m, 2H), 1.42-1.27 (m, 1H)。

example 194 Compound 214 ((2)R) -1- [4- [1- (4, 5-dichloro-2-hydroxyphenyl) -2, 2-difluoroethyl ]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one)

Step a:

4- [1- (4, 5-dichloro-2-methoxyphenyl) -2-oxoethyl stirred at-70 DEG C]To a solution of tert-butyl piperidine-1-carboxylate (intermediate 49, example 49) (0.30 g, 0.75 mmol) in DCM (3 mL) was added DAST (0.72 g, 4.47 mmol) dropwise. The resulting mixture was allowed to warm to room temperature and stirred under nitrogen for 16 hours. The reaction was quenched with water (30 mL) at 0 ℃ and extracted with EA (3X 35 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE/EA (5/1) to give 4- [1- (4, 5-dichloro-2-methoxyphenyl) -2, 2-difluoroethyl as a pale yellow oil]Piperidine-1-carboxylic acid tert-butyl ester (0.22 g, 57%): C₁₉H₂₅Cl₂F₂NO₃ [M + H]⁺Calculated lcms (esi): 424, 426 (3: 2), found 424, 426 (3: 2).

Step b:

4- [1- (4, 5-dichloro-2-methoxyphenyl) -2, 2-difluoroethyl stirred at 0 DEG C]To a solution of tert-butyl piperidine-1-carboxylate (0.22 g, 0.52 mmol) in DCM (5 mL) was added TFA (1 mL). The resulting mixture was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under reduced pressure. The crude product was used without further purification in the subsequent step: c ₁₄H₁₇Cl₂F₂NO [M + H]⁺Calculated lcms (esi): 324, 326 (3: 2), found 324, 326 (3: 2).

Step c:

to a stirred solution of 4- [1- (4, 5-dichloro-2-methoxyphenyl) -2, 2-difluoroethyl at room temperature]Piperidine (0.17 g, 0.52 mmol) and (4)R) -2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid (0.92 g, 0.63 mmol) and HOBt (0.11 g, 0.78 mmol) and Et₃EDCI (0.16 g, 0.79 mmol) was added portionwise to a solution of N (0.16 g, 1.57 mmol) in DMF (4 mL). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with water (40 mL) and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE/EA (2/1) to give 4- [1- (4, 5-dichloro-2-methoxyphenyl) -2, 2-difluoroethyl as a pale yellow oil]-1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidine (90 mg, 38%): C₂₀H₂₅Cl₂F₂NO₄ [M + H]⁺Calculated lcms (esi): 452, 454 (3: 2), found 452, 454 (3: 2).

Step d:

4- [1- (4, 5-dichloro-2-methoxyphenyl) -2, 2-difluoroethyl stirred at 0 DEG C]-1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidine (90 mg, 0.20 mmol) in DCM (1 mL) was added BBr dropwise ₃(0.15 g, 0.60 mmol). The resulting mixture was stirred at 0 ℃ for 30 minutes. The reaction was quenched with saturated NH at 0 deg.C₄Aqueous Cl solution was quenched. The resulting mixture was extracted with EA (3X 15 mL). The combined organic layers were washed with brine (2X 5 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: XBridge Shield RP18 OBD column 30X 150 mm, 5 μm; mobile phase A: having a NH concentration of 10 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 30% B to 55% B in 7 minutes; a detector: 254/220 nm; retention time: 6.5 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure to give compound 214 ((2) as an off-white solidR) -1- [4- [1- (4, 5-dichloro-2-hydroxyphenyl) -2, 2-difluoroethyl]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one) (21.2 mg, 25%): C₁₆H₁₉Cl₂F₂NO₄ [M + H]⁺Calculated lcms (esi): 398, 400 (3: 2), found 398, 400 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.33 (s, 1H), 6.96 (s, 1H), 6.26 (td, J = 56.3, 4.3 Hz, 1H), 4.62-4.34 (m, 2H), 4.07 (dd, J =45.8, 13.8 Hz, 1H), 3.78-3.59 (m, 2H), 3.39-3.32 (m, 1H), 3.08 (dt, J = 40.5, 12.8 Hz, 1H), 2.68 (dt, J = 41.1, 13.0 Hz, 1H), 2.23 (d, J = 11.2 Hz, 1H), 2.08 (d, J = 17.2 Hz, 1H), 1.67-1.25 (m, 2H), 1.26-0.98 (m, 1H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -119.02, -119.20.

example 195 Compound 209 (4- [ (()R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]-N- (2-hydroxyethyl) piperidine-1-carboxamide trifluoroacetic acid)

Step a:

stirring under nitrogen atmosphere at room temperatureS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ](piperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide (0.20 g, 0.47 mmol) and Et₃A mixture of N (96 mg, 0.95 mmol) in DCM (2 mL) was added 4-nitrophenyl carbonyl chloride (0.10 g, 0.57 mmol) dropwise. The reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was quenched with water (40 mL) and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (1/3) to give 4- ([ [ tert-butyl (hydroxy) -lambda 3-sulfanyl ] as an off-white solid]Amino group]4- (dihydroxyamino) phenyl (4, 5-dichloro-2-propoxycyclohexyl) methyl) piperidine-1-carboxylate (0.25 g, 75%): C₂₆H₃₁Cl₂N₃O₆S [M + H]⁺Calculated lcms (esi): 584, 586 (3: 2), measured 584, 586 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 8.30 (d, J = 8.7 Hz, 2H), 7.48 (s, 1H), 7.38 (t, J = 7.6 Hz, 2H), 7.19 (s, 1H), 6.20-6.05 (m, 1H), 5.47 (dd, J =17.4, 1.7 Hz, 1H), 5.36 (dd, J = 10.5, 1.5 Hz, 1H), 4.70-4.53 (m, 3H), 4.45-4.07 (m, 2H), 3.18-2.78 (m, 2H), 2.30-2.20 (m, 1H), 2.13-1.99 (m, 1H), 1.50-1.25 (m, 3H), 1.15 (s, 9H)。

step b:

4- [ (ii) to stirring at room temperatureR) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(R) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]4-Nitrophenyl piperidine-1-carboxylate (0.20 g, 0.34 mmol) in DMF (2 mL) was added 2-aminoethan-1-ol (0.40 g, 6.84 mmol). The reaction solution was stirred at 90 ℃ for 12 hours. The reaction mixture was diluted with water (30 mL) and extracted with EA (3X 35 mL). The combined organic layers were washed with brine (3X 10 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 25% aqueous ACN (plus 0.5% TFA) to give 4- [ ((r)) as a yellow solidR) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(R) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]-N- (2-hydroxyethyl) piperidine-1-carboxamide (0.12 g, 62%): C₂₂H₃₃Cl₂N₃O₄S [M + H]⁺Calculated lcms (esi): 506, 508 (3: 2), found 506, 508 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.45 (s, 1H), 7.17 (s, 1H), 6.16-6.04 (m, 1H), 5.50-5.29 (m, 2H), 4.67-4.48 (m, 3H), 4.14-3.92 (m, 2H), 3.58 (t, J = 5.8 Hz, 2H), 3.28 (t, J = 5.9 Hz, 2H), 2.86-2.62 (m, 2H), 2.14 (d, J = 13.5 Hz, 1H), 2.03-1.88 (m, 1H), 1.36-1.17 (m, 3H), 1.14 (s, 9H)。

step c:

stirring 4- [ (ii) (b) at room temperature under nitrogen atmosphereR) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]-N- (2-hydroxyethyl) piperidine-1-carboxamide (0.11 g, 0.21 mmol) and Pd (PPh)₃)₄(13 mg, 0.01 mmol) to a mixture in THF (2 mL) NaBH was added portionwise₄(16 mg, 0.43 mmol). The reaction mixture was stirred at room temperature for 30 minutes under nitrogen atmosphere. The resulting mixture was quenched with water (30 mL) and extracted with EA (3X 40 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. Filtering, concentrating the filtrate under reduced pressure to obtain 4- [ ((R) ()) in brown semisolid formR) - (4, 5-dichloro-2-hydroxyphenyl) ([ ((ii) ((iii))S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical ]-N- (2-hydroxyethyl) piperidine-1-carboxamide(66 mg, crude): C₁₉H₂₉Cl₂N₃O₄S [M + H]⁺Lcms (esi) calculated value of (a): 466, 468 (3: 2), found 466, 468 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.34 (s, 1H), 6.93 (s, 1H), 4.45-4.31 (m, 1H), 4.12-3.90 (m, 2H), 3.58 (t, J = 5.8 Hz, 2H), 3.28 (t, J = 5.9 Hz, 2H), 2.85-2.63 (m, 2H), 2.15 (d, J = 13.7 Hz, 1H), 2.04-1.90 (m, 1H), 1.36-1.17 (m, 3H), 1.14 (s, 9H)。

step d:

4- [ (ii) to stirring at room temperatureR) - (4, 5-dichloro-2-hydroxyphenyl) ([ ((ii) ((iii))S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]-N- (2-hydroxyethyl) piperidine-1-carboxamide (66 mg, 0.14 mmol) in THF (1 mL) was added aqueous HCl (4)N0.5 mL). The reaction solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column 19X 150 mm, 5 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 10% B to 33% B in 7 minutes; a detector: UV 220 nm; retention time: 4.7 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure to give compound 209 (4- [ (4-)) as an off-white solidR) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]-N- (2-hydroxyethyl) piperidine-1-carboxamide trifluoroacetic acid) (25 mg, 37% two-stage sum) C₁₅H₂₁Cl₂N₃O₃ [M + H]⁺Calculated lcms (esi): 362, 364 (3: 2), measured value, 362, 364 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.43 (s, 1H), 7.08 (s, 1H), 4.30-4.08 (m, 2H), 3.97 (d, J = 13.6 Hz, 1H), 3.69-3.42 (m, 2H), 3.28 (t, J = 5.8 Hz, 2H), 2.91-2.67 (m, 2H), 2.40-2.15 (m, 1H), 2.02-1.87 (m, 1H), 1.41-1.22 (m, 2H), 1.21-1.06 (m, 1H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.09。

EXAMPLE 196 Compound 215 ((2)R) -1- [6- [ amino (4, 5-dichloro-2-hydroxyphenyl) methyl group ]-3-azabicyclo [ 2 ]3.1.1]Heptane-3-yl radical]-2, 3-dihydroxypropane-1-ketotrifluoroacetic acid)

Step a:

to a stirred mixture of 1-bromo-4, 5-dichloro-2- (prop-2-en-1-yloxy) benzene (example 6, step b) (1.07 g, 3.80 mmol) in THF (15 mL) at-10 deg.C under a nitrogen atmosphere was added dropwisei-PrMgCl. LiCl (3.90 mL, 5.07 mmol, 1.3M THF solution). The resulting mixture was stirred at-10 ℃ for 30 minutes under nitrogen atmosphere. 6- [ methoxy (methyl) carbamoyl group was added dropwise to the above solution at-10 ℃ over 5 minutes]-3-azabicyclo [ 2 ]3.1.1]A solution of tert-butyl heptane-3-carboxylate (0.36 g, 1.27 mmol) in THF (2 mL). The resulting solution was stirred at-10 ℃ for an additional 2 hours under nitrogen. Reacting with saturated NH₄Aqueous Cl (20 mL) was quenched and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE/EA (1/1) to give 6- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl in the form of a pale yellow oil]-3-azabicyclo [ 2 ]3.1.1]Tert-butyl heptane-3-carboxylate (30 mg, 6%). C₂₁H₂₅Cl₂NO₄ [M + Na]⁺Calculated lcms (esi): 448, 450 (3: 2), found 448, 450 (3: 2); ¹H NMR (400 MHz, CDCl₃) δ 7.46 (d, J = 27.1 Hz, 1H), 6.99 (d, J = 27.9 Hz, 1H), 6.14-5.96 (m, 1H), 5.49-5.28 (m, 2H), 4.64-4.53 (m, 2H), 4.37-4.16 (m, 1H), 3.70-3.39 (m, 2H), 3.22 (dd, J = 11.6, 5.7 Hz, 1H), 2.80 (d, J = 27.5 Hz, 1H), 2.10 (d, J = 9.6 Hz, 1H), 1.63-1.55 (m, 1H), 1.50-1.43 (m, 10H), 1.37-1.19 (m, 1H)。

Step b:

to a stirred 6- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl group at room temperature]-3-azabicyclo [ 2 ]3.1.1]Tert-butyl heptane-3-carboxylate (30 mg, 0.07 mmol) and 2-methylpropane-2-sulfinamide (26 mg, 0.21 mmol) in THF (2 mL)Adding Ti (OEt)₄(96 mg, 0.42 mmol). The resulting solution was stirred at 70 ℃ for 16 hours under nitrogen atmosphere. After cooling to room temperature, the reaction was quenched with saturated NaHCO at room temperature₃Aqueous solution (30 mL) was quenched. The resulting mixture was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 6- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] in the form of a pale yellow oil][ (2-methylpropane-2-sulfinyl) imino]Methyl radical]-3-azabicyclo [ 2 ]3.1.1]Tert-butyl heptane-3-carboxylate (30 mg, crude), which was used in the next step without further purification: c₂₅H₃₄Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 529, 531 (3: 2), found 529, 531 (3: 2).

Step c:

stirring of 6- [ (1) at room temperatureE) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][ (2-methylpropane-2-sulfinyl) imino]Methyl radical]-3-azabicyclo [ 2 ]3.1.1]To a solution of tert-butyl heptane-3-carboxylate (30 mg, 0.06 mmol) in THF (1 mL) was added NaBH ₄(10 mg, 0.26 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (20 mL) at room temperature and extracted with EA (3X 20 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 6- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] in the form of a pale yellow oil][ (2-methylpropane-2-sulfinyl) amino group]Methyl radical]-3-azabicyclo [ 2 ]3.1.1]Tert-butyl heptane-3-carboxylate (40 mg, crude), which was used in the next step without further purification: c₂₅H₃₆Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 531, 533 (3: 2), found 531, 533 (3: 2).

Step d:

stirring of 6- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl at room temperature][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]-3-azabicyclo [3.1.1]Heptane-3-carboxylic acid tert-butyl ester (40 mg, 0.08 mm)ol) to a solution in DCM (2 mL) was added TFA (0.5 mL). The resulting solution was stirred at room temperature for 30 minutes. The reaction solution was saturated with NaHCO₃The aqueous solution (30 mL) was basified to pH 8 and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. Filtering, concentrating the filtrate under reduced pressure to obtain light yellow oil N- ([ 3-azabicyclo [3.1.1 ] s)]Heptane-6-yl][4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl) -2-methylpropane-2-sulfinamide (40 mg, crude), which was used directly in the next step without further purification. C₂₀H₂₈Cl₂N₂O₂S [M + H]⁺Lcms (esi) calculated value of (a): 431 and 433 (3: 2), found 431 and 433 (3: 2).

Step e:

stirring at room temperature (4)R) To a solution of (E) -2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid (20 mg, 0.14 mmol) and HATU (71 mg, 0.19 mmol) in DMF (1 mL) was addedN- ([ 3-azabicyclo ], [ 2 ]3.1.1]Heptane-6-yl radical][4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl) -2-methylpropane-2-sulfinamide (40 mg, 0.09 mmol) and Et₃N (28 mg, 0.28 mmol). The reaction was stirred at room temperature for 30 minutes. The reaction was purified by reverse phase chromatography eluting with 55% aqueous ACN (plus 0.05% TFA) to afford as a pale yellow oilN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([3-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]-3-azabicyclo [ 2 ]3.1.1]Heptane-6-yl radical]) Methyl radical]2-methylpropane-2-sulfinamide (10 mg, 26% of the total of the four stages): C₂₆H₃₆Cl₂N₂O₅S [M + H]⁺Calculated lcms (esi): 559, 561 (3: 2), found 559, 561 (3: 2).

Step f:

at room temperature with stirring N- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([3-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]-3-azabicyclo [ 2 ]3.1.1]Heptane-6-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide (10 mg, 0.02 mmol) and Pd (PPh)₃)₄(1 mg, 0.001 mmol) in THF (1)mL) was added NaBH₄(1.3 mg, 0.03 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The resulting mixture was washed with saturated NH₄Aqueous Cl (1 mL) was quenched and concentrated under reduced pressure to give a brown solidN-((4, 5-dichloro-2-hydroxyphenyl) (3- ((4)R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl) -3-azabicyclo [ 2 ], [3.1.1]Heptan-6-yl) methyl) -2-methylpropane-2-sulfinamide (10 mg, crude), which was used in the next step without further purification: c₂₃H₃₂Cl₂N₂O₅S [M + H]⁺Calculated lcms (esi): 519, 521 (3: 2), found 519, 521 (3: 2).

Step g:

at room temperature with stirringN-((4, 5-dichloro-2-hydroxyphenyl) (3- ((4)R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl) -3-azabicyclo [ 2 ], [3.1.1]Heptane-6-yl) methyl) -2-methylpropane-2-sulfinamide (10 mg, 0.02 mmol) in 1, 4-dioxane (1 mL) was added aqueous HCl (4)N1 mL). The resulting mixture was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: sunfire Prep C18 OBD column, 10 μm, 19X 250 mm; mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 10% B to 30% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.50 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 215 ((2) as an off-white solid R) -1- [6- [ amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]-3-azabicyclo [ 2 ]3.1.1]Heptane-3-yl]-2, 3-dihydroxypropan-1-one trifluoroacetic acid) (3.3 mg, 38% of the total of the two steps): C₁₆H₂₀Cl₂N₂O₄ [M + H]⁺Lcms (esi) calculated value of (a): 375, 377 (3: 2), found 375, 377 (3: 2); ¹H NMR (400 MHz, CD₃OD): ¹H NMR δ 7.65-7.46 (m, 1H), 7.09 (dd, J = 6.9, 4.3 Hz, 1H), 4.85-4.45 (m, 2H), 4.25-3.87 (m, 1H), 3.87-3.62 (m, 4H), 3.62-3.40 (m, 1H), 3.10-2.97 (m, 1H), 2.78-2.55 (m, 1H), 2.46-2.27 (m, 1H), 2.27-2.06 (m, 1H), 1.59-1.41 (m, 1H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.23.

example 197 Compound 217 (1- (4- ((R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) -2, 3-dihydroxy-2-methylpropan-1-one isomer 1) Compound 218 (1- (4- ((R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) -2, 3-dihydroxy-2-methylpropan-1-one isomer 2)

Step a:

separation of 1- [4- [ (ii) by preparative chiral HPLC under the following conditionsR) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidin-1-yl radical]-2, 3-dihydroxy-2-methylpropan-1-one trifluoroacetic acid (compound 201, example 191) (55 mg) column: CHIRALPAK IG, 2X 25 cm, 5 μm; mobile phase A: hexane (plus 0.2% IPA), mobile phase B: EtOH; flow rate: 20 mL/min; gradient: from 30% B to 30% B in 20 minutes; a detector: UV of 220/254 nm; retention time: RT (reverse transcription)₁12.76 minutes; RT (reverse transcription)₂17.37 minutes; injection volume 0.3 mL.

The faster eluting enantiomer was obtained as compound 217 (1- (4- ((R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) -2, 3-dihydroxy-2-methylpropan-1-one isomer 1) (10 mg, 24%) as an off-white solid at 12.76 min: (C.sub. ₁₆H₂₂Cl₂N₂O₄ [M + H]⁺Lcms (esi) calculated: 377, 379 (3: 2), found 377, 379 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.21 (s, 1H), 6.86 (s, 1H), 4.74-4.45 (m, 2H), 3.89 (d, J = 7.7 Hz, 1H), 3.71 (d, J = 11.2 Hz, 1H), 3.56 (d, J = 11.2 Hz, 1H), 3.04-2.37 (m, 2H), 2.15-1.93 (m, 2H), 1.48-1.40 (m, 1H), 1.38 (s, 3H), 1.33-1.09 (m, 2H)。

the slower eluting enantiomer was obtained as compound 218 (1- (4- ((R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) -2, 3-dihydroxy-2-methylpropan-1-one iso-isomer as an off-white solid at 17.37 minutesStructure 2) (15 mg, 36%) C₁₆H₂₂Cl₂N₂O₄ [M + H]⁺Lcms (esi) calculated value: 377, 379 (3: 2), found 377, 379 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 6.86 (s, 1H), 4.74-4.45 (m, 1H), 3.90 (d, J = 7.8 Hz, 1H), 3.71 (d, J = 11.2 Hz, 1H), 3.63-3.41 (m, 2H), 3.08-2.44 (m, 2H), 2.01 (dd, J = 34.1, 10.7 Hz, 2H), 1.50-1.42 (m, 1H), 1.38 (s, 3H), 1.34-1.06 (m, 2H)。

example 198 Compound 219 (3- [4- [ (()R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]Azetidine-3-ol trifluoroacetic acid)

Step a:

to a stirred 1- [ (tert-butoxy) carbonyl group at room temperature](87 mg, 0.40 mmol) of-3-hydroxyazetidine-3-carboxylic acid, EDCI (96 mg, 0.50 mmol) and HOBt (67 mg, 0.50 mmol) in DMF (2 mL) was addedS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.14 g, 0.34 mmol) and Et₃N (0.10 g, 1.00 mmol). The reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was diluted with water (20 mL) and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 3- [4- [ (R) as an off-white solid R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidine-1-carbonyl]-3-Hydroxyazetidine-1-carboxylic acid tert-butyl ester (0.18 g, crude): C₂₈H₄₁Cl₂N₃O₆S [M + H]⁺Calculated lcms (esi): 618, 620 (3: 2), found 618, 620 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.46 (s, 1H), 7.17 (s, 1H), 6.15-6.04 (m, 1H), 5.45 (d, J = 17.3 Hz, 1H), 5.34 (d, J = 10.6 Hz, 1H), 4.66-4.60 (m, 2H), 4.58-4.26 (m, 4H), 3.98-3.76 (m, 3H), 3.11-2.90 (m, 1H), 2.75-2.56 (m, 1H), 2.23-2.13 (m, 1H), 2.11-2.00 (m, 1H), 1.46 (s, 9H), 1.39-1.17 (m, 3H), 1.14 (s, 9H)。

step b:

stirring 3- [4- [ (C) at room temperature under nitrogen atmosphereR) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidine-1-carbonyl]-3-Hydroxyazetidine-1-carboxylic acid tert-butyl ester (0.18 g, 0.29 mmol) and Pd (PPh)₃)₄(17 mg, 0.02 mmol) in THF (2 mL) NaBH was added portionwise₄(22 mg, 0.58 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. The resulting mixture was washed with H at room temperature₂O (2 mL) was quenched and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. Filtering, concentrating the filtrate under reduced pressure to obtain 3- [4- [ (R) ((R))R) - (4, 5-dichloro-2-hydroxyphenyl) ([ ((ii) ((iii))S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidine-1-carbonyl]-3-Hydroxyazetidine-1-carboxylic acid tert-butyl ester (90 mg, crude): C₂₅H₃₇Cl₂N₃O₆S [M + H]⁺Calculated lcms (esi): 578, 580 (3: 2), found 578, 580 (3: 2).

Step c:

stirring 3- [4- [ (ii) at room temperatureR) - (4, 5-dichloro-2-hydroxyphenyl) ([ ((ii) ((iii))S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidine-1-carbonyl](iv) -3-Hydroxyazetidine-1-carboxylic acid tert-butyl ester (90 mg, 0.15 mmol) in THF (1 mL) was added dropwise aqueous HCl (4)N0.50 mL). The reaction mixture was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column 30X 150 mm, 5 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 5% B to 15% B in 7 minutes; a detector: UV 220 nm; retention time: 6.42 minutes. Collecting the fractions containing the desired product, concentrating under reduced pressure to brownThe compound 219 (3- [4- [ (iii))R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]Azetidin-3-ol trifluoroacetic acid) (38 mg, 50%): C₁₆H₂₁Cl₂N₃O₃[M + H]⁺Calculated lcms (esi): 374, 376 (3: 2), found 374, 376 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.44 (s, 1H), 7.09 (s, 1H), 4.71-4.40 (m, 3H), 4.25-3.88 (m, 3H), 3.18-2.93 (m, 1H), 2.83-2.59 (m, 1H), 2.48-2.30 (m, 1H), 2.03 (t, J = 12.5 Hz, 1H), 1.49-1.12 (m, 4H)。

in a manner analogous to that described for compound 219, fromS)-N-((R) Starting with- (2- (allyloxy) -4, 5-dichlorophenyl) (piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide and the corresponding acid (which is prepared as described herein or is available from commercial sources), the compounds in table 1d below are prepared.

TABLE 1d

Example 199 Compound 220 (1- [4- [ (II))R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]-3- (hydroxymethyl) azetidin-3-ol)

Step a:

4- (C) to stirring at room temperatureR) - (2- (allyloxy) -4, 5-dichlorophenyl) (((s))S) -tert-butylsulfinyl) amino) methyl) piperidine-1-carboxylic acid 4-nitrophenyl ester (0.35 g, crude) and a solution of 3- (hydroxymethyl) azetidin-3-ol (0.13 g, 1.24 mmol) in 1, 4-dioxane (4 mL) DIEA (1.60 g, 12.40 mmol) was added dropwise. The reaction mixture was stirred at 90 ℃ for 12 hours. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with EA (3X 25 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 50% aqueous ACN (plus 0.5% TFA) to give (S)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([1- [ 3-hydroxy-3- (hydroxymethyl) azetidine-1-carbonyl)]Piperidin-4-yl radical]) Methyl radical]2-methylpropane-2-sulfinamide (0.14 g, 38%): C₂₄H₃₅Cl₂N₃O₅S [M + H]⁺Calculated lcms (esi): 548, 550 (3: 2), found 548, 550 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.22 (s, 1H), 6.97 (s, 1H), 6.09-5.96 (m, 1H), 5.48-5.31 (m, 2H), 4.63-4.49 (m, 2H), 4.45-4.32 (m, 1H), 4.08-3.82 (m, 8H), 2.80-2.59 (m, 2H), 2.04-1.84 (m, 2H), 1.32-1.22 (m, 3H), 1.15 (s, 9H)。

step b:

stirring under nitrogen atmosphere at room temperature S)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([1- [ 3-hydroxy-3- (hydroxymethyl) azetidine-1-carbonyl)]Piperidin-4-yl]) Methyl radical]-2-methylpropane-2-sulfinamide (0.14 g, 0.25 mmol) and Pd (PPh)₃)₄(15 mg, 0.01 mmol) in THF (2 mL) NaBH was added portionwise₄(19 mg, 0.51 mmol). The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was quenched with water (3 mL) at room temperature and concentrated under reduced pressure to give (A) as a yellow solidS)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) ([1- [ 3-hydroxy-3- (hydroxymethyl) azetidine-1-carbonyl)]Piperidin-4-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide (0)14 g, crude) C₂₁H₃₁Cl₂N₃O₅S [M + H]⁺Calculated lcms (esi): 508, 510 (3: 2), found, 508, 50 (3: 2)

Step c:

stirring at room temperature (S)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) ([1- [ 3-hydroxy-3- (hydroxymethyl) azetidine-1-carbonyl)]Piperidin-4-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide (0.14 g, crude) in THF (1 mL) aqueous HCl (4) was added dropwiseN0.5 mL, respectively). The reaction solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column 19X 150 mm, 5 μm; mobile phase A: having a NH concentration of 10 mmol/L ₄HCO₃Water, mobile phase B: ACN; flow rate: 20 mL/min; gradient: from 13% B to 35% B in 7 minutes; a detector: UV 220 nm; retention time: 7.4 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure to give compound 220 (1- [4- [ (1- [)) as an off-white solidR) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]-3- (hydroxymethyl) azetidin-3-ol) (16 mg, 14% of two steps in total): C₁₇H₂₃Cl₂N₃O₄ [M + H]⁺Calculated lcms (esi): 404, 406 (3: 2), found 404, 406 (3: 2); ¹H NMR (400 MHz, CD₃OD) δ 7.21 (s, 1H), 6.86 (s, 1H), 4.27-3.95 (m, 3H), 3.92-3.70 (m, 4H), 3.58 (s, 2H), 2.75 (dt, J = 25.9, 12.7 Hz, 2H), 2.09-1.87 (m, 2H), 1.49-1.09 (m, 3H)。

EXAMPLE 200 Compound 221 (5- [4- [ (R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl ] piperidin-1-carbonyl ] piperidin-2-one isomer 1); the compound 222 (5- [4- [ (R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl ] piperidine-1-carbonyl ] piperidin-2-one isomer 2)

Step a:

by chiral preparative HPLC in the presence ofSeparating 5- [4- [ (ii) under the condition of low temperatureR) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]Piperidin-2-one (35 mg, 0.09 mmol) column: chiralpak IC, 2X 25 cm, 5 μm; mobile phase A: hexane (0.2% IPA), mobile phase B: EtOH; flow rate: 20 mL/min; gradient: from 40% B to 40% B in 26 minutes; a detector: 220/254 nm; retention time: RT (reverse transcription)₁18.17 minutes; RT (reverse transcription) ₂22.14 minutes. The faster eluting enantiomer was obtained as compound 222 (5- [4- [ (R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) in the form of an off-white solid at 18.17 min]Piperidine-1-carbonyl]Piperidin-2-one isomer 2) (6.7 mg, 19%): C₁₈H₂₃Cl₂N₂O₃ [M + H]⁺Calculated lcms (esi): 400, 402 (3: 2), found 400, 402 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 6.89 (s, 1H), 4.57 (dd, J = 39.7, 13.3 Hz, 1H), 4.10 (dd, J = 37.1, 13.8 Hz, 1H), 3.92 (t, J = 8.5 Hz, 1H), 3.51-3.36 (m, 1H), 3.23-2.97 (m, 2H), 2.68-2.50 (m, 1H), 2.47-2.35 (m, 2H), 2.15-1.84 (m, 4H), 1.50 (t, J = 15.3 Hz, 1H), 1.40-1.04 (m, 3H)。

the slower eluting enantiomer was obtained as compound 221 (5- [4- [ (R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) in the form of an off-white solid at 22.142 min]Piperidine-1-carbonyl]Piperidin-2-one isomer 1) (6.4 mg, 18%): C₁₈H₂₃Cl₂N₂O₃ [M + H]⁺Calculated lcms (esi): 400, 402 (3: 2), found 400, 402 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.23 (d, J = 7.0 Hz, 1H), 6.88 (d, J = 2.2 Hz, 1H), 4.57 (dd, J = 38.7, 13.3 Hz, 1H), 4.10 (dd, J = 38.9, 13.8 Hz, 1H), 3.96-3.84 (m, 1H), 3.53-3.35 (m, 1H), 3.24 -2.99 (m, 2H), 2.71-2.49 (m, 1H), 2.46-2.32 (m, 2H), 2.13-1.83 (m, 4H), 1.60-1.42 (m, 1H), 1.38-1.08 (m, 3H)。

EXAMPLE 201 Compound 296 (4- [4- [ (R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl ] piperidine-1-carbonyl ] pyrrolidin-2-one isomer 1); compound 246 (4- [4- [ (R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl ] piperidine-1-carbonyl ] pyrrolidin-2-one isomer 2)

Step a:

separation of 4- [4- [ (ii) by chiral preparative HPLC under the following conditionsR) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]Pyrrolidin-2-one trifluoroacetic acid (80 mg, 0.21 mmol) column: CHIRALPAK IC, 2X 25 cm, 5 μm; mobile phase A: MTBE (plus 0.2% IPA), mobile phase B: EtOH; flow rate: 16 mL/min; gradient: from 30% B to 30% B in 26 minutes; a detector: UV 220/254 nm; retention time: RT (reverse transcription) ₁14.14 minutes; RT (reverse transcription)₂22.44 minutes.

The faster eluting enantiomer at 14.14 min was obtained as compound 296 (4- [4- [ (R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) in the form of an off-white solid at 14.14 min]Piperidine-1-carbonyl]Pyrrolidin-2-one isomer 1) (free amine) (20.6 mg, 32%): C₁₇H₂₁Cl₂N₃O₃ [M + H]⁺Calculated lcms (esi): 386, 388 (3: 2), found 386, 388 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.23 (d, J =6.0 Hz, 1H), 6.87 (d, J = 2.3 Hz, 1H), 4.57 (dd, J = 38.6, 13.4 Hz, 1H), 4.13-3.84 (m, 2H), 3.84-3.67 (m, 1H), 3.67-3.57 (m, 1H), 3.57-3.43 (m, 1H), 3.16-2.93 (m, 1H), 2.72-2.45 (m, 3H), 2.13-1.95 (m, 2H), 1.49 (t, J = 16.3 Hz, 1H), 1.41-1.06 (m, 2H)。

the slower eluting enantiomer at 22.44 min was obtained as compound 246 (4- [4- [ (R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) in the form of an off-white solid at 22.44 min]Piperidine-1-carbonyl]Pyrrolidin-2-one isomer 2) (18.9 mg, 30%) C₁₇H₂₁Cl₂N₃O₃ [M + H]⁺Calculated lcms (esi): 386, 388 (3: 2), found 386, 388 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 6.87 (d, J = 1.7 Hz, 1H), 4.57 (dd, J = 38.4, 13.4 Hz, 1H), 4.13-3.84 (m, 2H), 3.81-3.67 (m, 1H), 3.67-3.43 (m, 2H), 3.18-2.94 (m, 1H), 2.74-2.44 (m, 3H), 2.11-1.91 (m, 2H), 1.49 (d, J = 13.4 Hz, 1H), 1.35-1.04 (m, 2H)。

example 202 Compound 225 ((2)R)-1-((3aR,5R,6aS) -5- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) hexahydrocyclopenta [ c]Pyrrole-2 (1)H) -yl) -2, 3-dihydroxypropan-1-one

Step a:

stirring (3 a) at room temperature under nitrogen atmosphereR,5R,6aS) -2- (tert-butoxycarbonyl) -hexahydro-1H-cyclopenta [ alpha ], [c]A mixture of pyrrole-5-carboxylic acid (0.10 g, 0.39 mmol), EDCI (0.11 g, 0.59 mmol) and HOBt (79 mg, 0.59 mmol) in DMF (2 mL) was added in portions to Et₃N (59 mg, 0.59 mmol) and N, ODimethylhydroxylamine HCl (36 mg, 0.59 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The resulting mixture was quenched with water (30 mL) at room temperature and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (2X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 60% aqueous ACN (plus 0.05% TFA) to give (3 a) as a colorless oilR,5R,6aS) -5- [ methoxy (methyl) carbamoyl]-hexahydro-1H-cyclopenta [ alpha ], [c]Pyrrole-2-carboxylic acid tert-butyl ester (0.10 g, 81%) C₁₅H₂₆N₂O₄ [M + H]⁺Calculated lcms (esi): 299, measured value 299;¹H NMR (400 MHz, CDCl₃) δ 4.84-4.55 (m, 2H), 3.70 (s, 3H), 3.60-3.48 (m, 2H), 3.35-3.25 (m, 1H), 3.22 (s, 3H), 2.76-2.62 (m, 2H), 2.21-2.09 (m, 2H), 1.84-1.68 (m, 2H), 1.45 (s, 9H)。

step b:

1-bromo-4, 5-dichloro-2- (prop-2-en-1-yloxy) benzene (0.47 g, 1) was added at-5 ℃ over 15 minutes under nitrogen68 mmol) in THF (10 mL) was addedi-PrMgCl. LiCl (1.30 mL, 1.68 mmol, 1.3M in THF). After stirring for another 30 minutes, (3 a) was added dropwiseR,5R,6aS) -5- [ methoxy (methyl) carbamoyl]-hexahydro-1H-cyclopenta [ alpha ], [c]A solution of tert-butyl pyrrole-2-carboxylate (0.10 g, 0.34 mmol) in THF (5 mL). The reaction mixture was stirred at-5 ℃ for 0.5 h under nitrogen. The resulting mixture was washed with saturated NH at-5 deg.C₄Aqueous Cl (40 mL) was quenched and extracted with EA (2X 100 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography eluting with 70% aqueous ACN (0.05% TFA) to afford (3 a) as a yellow oilR,5R,6aS) -5- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl]-hexahydro-1H-cyclopenta [ c]Pyrrole-2-carboxylic acid tert-butyl ester (32 mg, 22%): C₂₂H₂₇Cl₂NO₄ [M + H]⁺Calculated lcms (esi): 440, 442 (3: 2), found 440, 442 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.66 (s, 1H), 6.98 (s, 1H), 6.11-6.00 (m, 1H), 5.51-5.37 (m, 2H), 4.70 (d, J = 5.6 Hz, 2H), 3.75 (dd, J = 20.7, 11.3 Hz, 1H), 3.64-3.39 (m, 2H), 3.31-3.22 (d, J = 11.2 Hz, 2H), 2.75-2.56 (m, 2H), 2.23-2.11 (m, 2H), 1.84-1.67 (m, 2H), 1.47 (s, 9H)。

step c:

stirring (3 a) at room temperature under nitrogen atmosphereR,5R,6aS) -5- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl]-hexahydro-1H-cyclopenta [ alpha ], [c]Pyrrole-2-carboxylic acid tert-butyl ester (50 mg, 0.11 mmol) and Ti (OEt)₄(0.10 g, 0.45 mmol) in THF (5 mL) was added tert-butanesulfinamide (21 mg, 0.17 mmol) portionwise. The reaction solution was warmed to 70 ℃ and stirred under nitrogen for 24 hours. After cooling to room temperature, the resulting solution was quenched with water (60 mL) and extracted with EA (2X 80 mL). The combined organic layers were washed with brine (3X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to obtain crude (3aR,5R,6aS) -5-((2- (allyloxy) -4, 5-dichlorophenyl) ((tert-butylsulfinyl) imino) methyl) hexahydrocyclopenta [ 2 ], [ solution of (i) and (ii) a salt thereofc]Pyrrole-2 (1)H) -tert-butyl formate. The crude product was used without further purification in the subsequent step: c ₂₆H₃₆Cl₂N₂O₄S [M + H]⁺Lcms (esi) calculated value of (a): 543, 545 (3: 2), found 543, 545 (3: 2).

Step d:

stirring (3 a) at room temperature under nitrogen atmosphereR,5R,6aS) -5- ((2- (allyloxy) -4, 5-dichlorophenyl) ((tert-butylsulfinyl) imino) methyl) hexahydrocyclopenta [ 2 ]c]Pyrrole-2 (1)H) -tert-butyl formate (crude) in THF (2 mL) NaBH was added portionwise₄(5 mg, 0.13 mmol). After stirring for 1 hour, the resulting mixture was quenched with water (20 mL) at room temperature and extracted with EA (2X 30 mL). The combined organic layers were washed with brine (2X 15 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give crude (3aR,5R,6aS) -5- ((2- (allyloxy) -4, 5-dichlorophenyl) (1, 1-dimethylethylenesulfonamido) methyl) hexahydrocyclopenta [ c ] c]Pyrrole-2 (1)H) -tert-butyl formate. The crude product was used without further purification in the subsequent step: c₂₆H₃₈Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 545, 547 (3: 2), found 545, 547 (3: 2).

Step e:

to stirred (3aR,5R,6aS) -5- ((2- (allyloxy) -4, 5-dichlorophenyl) (1, 1-dimethylethylenesulfonamido) methyl) hexahydrocyclopenta [ 2 ], [c]Pyrrole-2 (1)H) Tert-butyl formate (crude) in DCM (2 mL) was added TFA (0.5 mL) dropwise. After stirring at room temperature for 1 hour, the reaction solution was washed with saturated NaHCO ₃The aqueous solution was basified to pH 8 and extracted with EA (2X 50 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography eluting with 70% aqueous ACN to give a yellow oilN-[(3aR,5R,6aS) -octahydrocyclopenta [ 2 ]c]Pyrrol-5-yl [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]2-methylpropane-2-sulfinamide (18 mg, 61% of the total of the three steps): C₂₁H₃₀Cl₂N₂O₂S [M + H]⁺Calculated lcms (esi): 445, 447 (3: 2), found 445, 447 (3: 2).

Step f:

stirring at room temperature (4)R) To a solution of (9 mg, 0.06 mmol) of (2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid and (23 mg, 0.06 mmol) of HATU in DMF (1 mL) was addedN-[(3aR,5R,6aS) -octahydrocyclopenta [ alpha ], [ alpha ] and [ alpha ], [ alpha ] anc]Pyrrol-5-yl [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]-2-methylpropane-2-sulfinamide (18 mg, 0.04 mmol) and Et₃N (16 mg, 0.16 mmol). The reaction solution was stirred at room temperature for 2 hours. The resulting solution was quenched with water (20 mL) at room temperature and extracted with EA (2X 20 mL). The combined organic layers were washed with brine (2X 15 mL) and dried over anhydrous Na₂SO₄And (5) drying. Filtering, and concentrating the filtrate under reduced pressure to obtainN- ((4, 5-dichloro-2-hydroxyphenyl) ((3 a) R,5R,6aS)-2-((R) 2, 2-dimethyl-1, 3-dioxolane-4-carbonyl) octahydrocyclopenta [ 2 ], [ 2, 2-dimethyl-1, 3-dioxolanec]Pyrrol-5-yl) methyl) -2-methylpropane-2-sulfinamide. The resulting mixture was used without further purification in the subsequent step C₂₇H₃₈Cl₂N₂O₅S [M + H]⁺Lcms (esi) calculated value of (a): 573, 575 (3: 2), found 573, 575 (3: 2).

Step g:

under nitrogen atmosphere at room temperature with stirringN- ((4, 5-dichloro-2-hydroxyphenyl) ((3 a)R,5R,6aS)-2-((R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl) octahydrocyclopenta [ 2, 2-dimethyl ] -octahydrocyclopenta [ alpha ], [ beta ] -n-methyl-2, 3-dioxolane-4-carbonylc]Pyrrol-5-yl) methyl) -2-methylpropane-2-sulfinamide (crude) and Pd (PPh)₃)₄(6 mg, 0.005 mmol) in THF (2 mL) NaBH was added₄(4 mg, 0.11 mmol). After stirring at room temperature for 1 hour, the resulting mixture was washed with saturated NH at room temperature₄Aqueous Cl (1 mL) was quenched and concentrated under reduced pressure to giveN- ((4, 5-dichloro-2-hydroxyphenyl) ((3 a)R,5R,6aS)-2-((R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl) octahydrocyclopenta [ 2, 2-dimethyl ] -octahydrocyclopenta [ alpha ], [ beta ] -n-methyl-2, 3-dioxolane-4-carbonylc]Pyrrol-5-yl) methyl) -2-methylpropane-2-sulfinamide. The crude product was used without further purification in the subsequent step: c₂₄H₃₄Cl₂N₂O₅S [M + H]⁺Calculated lcms (esi): 533, 535 (3: 2), found 533, 535 (3: 2).

Step h:

to a stirred mixture of N- ((4, 5-dichloro-2-hydroxyphenyl) ((3aR,5R,6aS) -2- ((R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl) octahydrocyclopenta [ c ] at room temperature ]Pyrrol-5-yl) methyl) -2-methylpropan-2-sulfinamide (crude) to a mixture in THF (2 mL) aqueous HCl (6) was added dropwiseN2 mL). The reaction solution was stirred at room temperature for 2 hours. The reaction solution was stirred at room temperature for 1 hour. The resulting solution was diluted with EA (10 mL). The organic layer was washed with aqueous HCl (1)N3X 10 mL). The combined aqueous layers were washed with EA (3X 10 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: sunfire Prep C18 OBD column, 10 μm, 19X 250 mm; mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 5% B to 35% B in 7 minutes; a detector: UV 254 nm; retention time: 5.8 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 225 ((2) as an off-white solidR)-1-((3aR,5R,6aS) -5- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) hexahydrocyclopenta [ 2 ]c]Pyrrole-2 (1)H) -yl) -2, 3-dihydroxypropan-1-one) (0.6 mg, 4% of three steps in total): C₁₇H₂₂Cl₂N₂O₄ [M + H]⁺Calculated lcms (esi): 389, 391 (3: 2), found 389, 391 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.46 (s, 1H), 7.07 (s, 1H), 4.41-4.32 (m, 1H), 4.30-4.15 (m, 1H), 3.8-3.45 (m, 5H), 2.95-2.60 (m, 3H), 2.38-2.25 (m, 1H), 1.83-1.70 (m, 1H), 1.42-1.10 (m, 3H)。

EXAMPLE 203 Compound 226 (, (2R)-1-[4-[(R) -amino [ 5-chloro-4- (fluoromethyl)2-hydroxyphenyl radical]Methyl radical]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid)

A, step a:

under nitrogen atmosphere, stirring at room temperatureS)-N-[(R) - [ 4-bromo-5-chloro-2- (prop-2-en-1-yloxy) phenyl]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide (intermediate 24, example 24) (3.80 g, 6.42 mmol) and (tributylstannyl) methanol (3.09 g, 9.629 mmol) in dioxane (30 mL) to a solution of Pd (PPh) was added₃)₄(0.74 g, 0.64 mmol). The resulting mixture was stirred at 100 ℃ for 16 hours under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3X 50 mL). The combined organic layers were washed with brine (2X 50 mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with a solution containing 10 mmol/L NH₄HCO₃50% CH of₃CN aqueous solution is eluted, and the product is obtained in the form of light yellow semi-solid (A)S)-N-[(R) - [ 5-chloro-2-hydroxy-4- (hydroxymethyl) phenyl group]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]2-methylpropane-2-sulfinamide (1.80 g, 57%): C₂₃H₃₅ClN₂O₆S[M + H]⁺Calculated lcms (esi): 503, 505 (3: 1) measured value: 503, 505 (3: 1);¹H NMR (400 MHz, CDCl₃) δ 7.11-6.96 (m, 2H), 4.74-4.65 (m, 3H), 4.65-4.54 (m, 1H), 4.51-4.40 (m, 0H), 4.41-4.26 (m, 3H), 4.24-4.16 (m, 1H), 4.11-4.02 (m, 1H), 3.09-2.83 (m, 2H), 2.59-2.35 (m, 2H), 2.14-1.93 (m, 2H), 1.44-1.33 (m, 6H), 1.20 (d, J = 7.1 Hz, 9H)。

step b:

stirring at room temperature under air atmosphereN-[(R) - [ 5-chloro-2-hydroxy-4- (hydroxymethyl) phenyl group ]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidine derivatives-4-yl]) Methyl radical]To a solution of-2-methylpropane-2-sulfinamide (120 mg, 0.239 mmol, 1.00 equiv.) in dioxane (0.50 mL) was added HCl (4M) (2.00 mL). The reaction was stirred at room temperature for 1 hour. The pH value is saturated NaHCO₃The aqueous solution was adjusted to 8. Then adding Boc thereto₂O (62 mg, 0.286 mmol, 1.20 equiv.) and Na₂CO₃(75.85 mg, 0.716 mmol, 3.00 equiv.). The reaction was stirred at room temperature for 16 hours. The reaction was diluted with EtOAc (30 mL) and water (30 mL). The aqueous layer was extracted with EtOAc (3X 30 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to obtain N- [ (a) in the form of a pale yellow solidR) - [ 5-chloro-2-hydroxy-4- (hydroxymethyl) phenyl group]([1-[(2R) -2, 3-dihydroxypropanoyl group]Piperidin-4-yl radical]) Methyl radical]C tert-butyl carbamate (100 mg, 91.34%)₂₁H₃₁ClN₂O₇ [M + H]⁺Calculated lcms (esi): 459, 461 (3: 1) found: 459, 461 (3: 1).

Step c:

at room temperature with stirringN-[(R) - [ 5-chloro-2-hydroxy-4- (hydroxymethyl) phenyl group]([1-[(2R) -2, 3-dihydroxypropanoyl group]Piperidin-4-yl radical]) Methyl radical]To a solution of tert-butyl carbamate (0.80 g, 1.74 mmol) and 2, 2-dimethoxypropane (0.36 g, 3.49 mmol) in acetone (10 mL) was added TsOH (30 mg, 0.17 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was diluted with EtOAc (30 mL) and water (30 mL). The aqueous layer was extracted with EtOAc (3X 30 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with a solution containing 10 mmol/L NH₄HCO₃38% CH of₃Eluting with CN water solution to obtain the final product in the form of light yellow solidN-[(R) - [ 5-chloro-2-hydroxy-4- (hydroxymethyl) phenyl group]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]Tert-butyl carbamate (0.50 g, 57%): C₂₄H₃₅ClN₂O₇ [M + H]⁺Calculated lcms (esi): 499, 501 (3: 1) found: 499, 501 (3: 1)； ¹H NMR (400 MHz, CDCl₃) δ 7.07-6.86 (m, 2H), 5.66-5.32 (m, 1H), 4.74-4.52 (m, 4H), 4.52-4.34 (m, 2H), 4.27-4.03 (m, 2H), 3.96-3.53 (m, 1H), 3.12-2.80 (m, 1H), 2.69-2.42 (m, 1H), 2.13-1.84 (m, 2H), 1.81-1.61 (m, 1H), 1.52-1.36 (m, 15H) and 2- [ (m, 1H)R) - [ (tert-Butoxycarbonyl) amino group]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]-4-chloro-5- (hydroxymethyl) phenyl tert-butyl carbonate in the form of a pale yellow solid (0.21 g, 20%): C₂₉H₄₃ClN₂O₉ [M + H]⁺Calculated lcms (esi): 599, 601 (3: 1) found: 599, 601 (3: 1).¹H NMR (400 MHz, CDCl₃) δ 7.38 (s, 1H), 7.08-6.92 (m, 1H), 5.11-4.95 (m, 1H), 4.79-4.72 (m, 1H), 4.74-4.56 (m, 3H), 4.56-4.35 (m, 3H), 4.25-4.05 (m, 1H), 3.93-3.56 (m, 2H), 3.14-2.76 (m, 1H), 2.80-2.41 (m, 1H), 2.15-1.69 (m, 2H), 1.59 (s, 6H), 1.49-1.36 (m, 18H)。

Step d:

under nitrogen atmosphere at room temperature with stirringN-[(R) - [ 5-chloro-2-hydroxy-4- (hydroxymethyl) phenyl group]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical ]To a solution of tert-butyl carbamate (65 mg, 0.13 mmol) in DCM (2 mL) was added DAST (42 mg, 0.26 mmol). The reaction was stirred at room temperature for 1 hour under nitrogen atmosphere. The reaction was quenched with water (20 mL). The aqueous layer was extracted with DCM (3X 20 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. Filtering, concentrating the filtrate under reduced pressure to obtain light yellow oilN-[(R) - [ 5-chloro-4- (fluoromethyl) -2-hydroxyphenyl group]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]Tert-butyl carbamate (65 mg, crude), which was used in the next step without further purification: c₂₄H₃₄ClFN₂O₆ [M + H]⁺Calculated lcms (esi): 501, 503 (3: 1), found 501, 503 (3: 1).

Step e:

at room temperature with stirringN-[(R) - [ 5-chloro-4- (fluoromethyl) -2-hydroxyphenyl group]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]To a solution of tert-butyl carbamate (65 mg, 0.13 mmol) in DCM (2 mL) was added TFA (0.5 mL). The reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xselect CSH OBD column 30 × 150 mm 5 μm, n; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 5% B to 15% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.32 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 226 as an off-white solid (, (R-C) 2R)-1-[4-[(R) -amino [ 5-chloro-4- (fluoromethyl) -2-hydroxyphenyl]Methyl radical]Piperidin-1-yl]-2, 3-dihydroxypropan-1-one trifluoroacetic acid) (12.9 mg, 21% of two steps in total) C₁₆H₂₂ClFN₂O₄ [M + H]⁺Lcms (esi) calculated value of (a): 361, 363 (3: 1), found 361, 363 (3: 1);¹H NMR (400 MHz, CD₃OD) δ 7.34 (s, 1H), 7.09 (s, 1H), 5.46 (d, J = 47.1 Hz, 2H), 4.75-4.44 (m, 2H), 4.33-3.98 (m, 2H), 3.85-3.54 (m, 2H), 3.19-2.92 (m, 1H), 2.77-2.48 (m, 1H), 2.48-2.29 (m, 1H), 2.10-1.81 (m, 1H), 1.52-0.99 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.10, -219.80。

example 204 Compound 227 (, (2R)-1-[4-[(R) -amino [ 5-chloro-4- (difluoromethyl) -2-hydroxyphenyl]Methyl radical]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid)

Step a:

stirring of 2- [ (ii) at room temperatureR) - [ (tert-Butoxycarbonyl) amino group]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]To a solution of-4-chloro-5- (hydroxymethyl) phenyl tert-butyl carbonate (example 203, step c) (0.21 g, 0.35 mmol) in DCM (3 mL) was added dess-martin reagent (0.16 g, 0.37 mmol).The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated Na at room temperature₂SO₃Aqueous solution (1 mL) was quenched. The resulting mixture was extracted with DCM (3X 20 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 55% aqueous ACN (plus 0.05% TFA) to give 2- [ ((r)) as a pale yellow solidR) - [ (tert-Butoxycarbonyl) amino group ]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl]) Methyl radical]-4-chloro-5-formylphenyl tert-butyl carbonate (0.12 g, 57%) C₂₉H₄₁ClN₂O₉ [M + H]⁺Calculated lcms (esi): 597, 599 (3: 1), found 597, 599 (3: 1);¹H NMR (400 MHz, DMSO-d ₆) δ 10.25 (s, 1H), 7.84-7.65 (m, 2H), 7.62-7.52 (m, 1H), 4.88-4.59 (m, 2H), 4.43-4.17 (m, 2H), 4.17-3.83 (m, 2H), 3.02-2.76 (m, 2H), 2.50-2.38 (m, 2H), 1.87-1.59 (m, 3H), 1.51 (d, J =5.2 Hz, 9H), 1.36 (s, 9H), 1.29 (s, 6H)。

step b:

stirring of 2- [ (ii) (b) at room temperature under nitrogen atmosphereR) - [ (tert-Butoxycarbonyl) amino group]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]To a solution of-4-chloro-5-formylphenyl tert-butyl carbonate (0.12 g, 0.20 mmol) in DCM (2 mL) was added DAST (65 mg, 0.40 mmol). The reaction was stirred at room temperature for 1 hour under nitrogen atmosphere. The reaction was quenched with water (20 mL). The aqueous layer was extracted with DCM (3X 20 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. Filtering, concentrating the filtrate under reduced pressure to obtain 2- [ (R) ((R))R) - [ (tert-Butoxycarbonyl) amino group]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]-4-chloro-5- (difluoromethyl) phenyl tert-butyl carbonate (0.12 g, crude), which was used in the next step without further purification: c₂₉H₄₁ClF₂N₂O₈ [M + H]⁺Calculated lcms (esi): 619, 621 (3: 1),found 619, 621 (3: 1).

Step c:

stirring of 2- [ (ii) at room temperatureR) - [ (tert-Butoxycarbonyl) amino group]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]To a solution of-4-chloro-5- (difluoromethyl) phenyl tert-butyl carbonate (0.12 g, 0.19 mmol) in DCM (3 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xselect CSH OBD column 30X 150 mm 5 μm; mobile phase a: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 5% B to 20% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.56 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 227 (a) (b) as an off-white solid2R)-1-[4-[(R) -amino [ 5-chloro-4- (difluoromethyl) -2-hydroxyphenyl]Methyl radical]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid) (36.5 mg, 37% of two steps in total): C₁₆H₂₁ClF₂N₂O₄ [M + H]⁺Calculated lcms (esi): 379, 381 (3: 1), found 379, 381 (3: 1);¹H NMR (400 MHz, CD₃OD) δ 7.43 (s, 1H), 7.23 (s, 1H), 7.00 (t, J = 54.7 Hz, 1H), 4.71-4.39 (m, 2H), 4.31-4.02 (m, 2H), 3.75-3.57 (m, 2H), 3.08 (dt, J = 44.4, 12.6 Hz, 1H), 2.67 (dt, J = 44.8, 12.9 Hz, 1H), 2.49-2.34 (m, 1H), 2.09-1.95 (m, 1H), 1.49-1.11 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.27, -117.12。

example 205 Compound 228 (5- [4- [ (()R) -amino (5-chloro-2-hydroxy-4-methylphenyl) methyl]Piperidine-1-carbonyl]-1H-pyridin-2-one)

Step a:

to stirred 6-oxo-1 at room temperature HPyridine-3-carboxylic acid (0.10 g, 0.75 mmol), HOBt (0.14 g, 1.00 mmol), EDCI (0.19 g, 1.00 mmol) inTo a mixture of DMF (2 mL) was addedS)-N-[(R) - [ 5-chloro-4-methyl-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide (0.20 g, 0.50 mmol) and Et₃N (0.15 g, 1.50 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (40 mL) and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 70% aqueous ACN (plus 0.05% TFA) and obtained as a pale yellow solid (S)-N-[(R) - [ 5-chloro-4-methyl-2- (prop-2-en-1-yloxy) phenyl][1- (6-oxo-1)H-pyridine-3-carbonyl) piperidin-4-yl]Methyl radical]2-methylpropane-2-sulfinamide (0.10 g, 31%): C₂₆H₃₄ClN₃O₄S [M + H]⁺Calculated lcms (esi): 520, 522 (3: 1), found 520, 522 (3: 1); ¹H NMR (400 MHz, CD₃Cl) δ 7.59 (s, 1H), 7.52 (d, J = 10.0 Hz, 1H), 7.10 (s, 1H), 6.76 (s, 1H), 6.57 (d, J = 9.4 Hz, 1H), 6.13-5.99 (m, 1H), 5.38 (dd, J = 28.6, 13.9 Hz, 2H), 4.66-4.48 (m, 2H), 4.46-4.09 (m, 3H), 2.95-2.66 (m, 2H), 2.36 (s, 3H), 2.23-1.95 (m, 2H), 1.53-1.19 (m, 3H), 1.15 (s, 9H)。

step b:

stirring at room temperature (S)-N-[(R) - [ 5-chloro-4-methyl-2- (prop-2-en-1-yloxy) phenyl][1- (6-oxo-1)H-pyridine-3-carbonyl) piperidin-4-yl]Methyl radical]-2-methylpropane-2-sulfinamide (0.10 g, 0.19 mmol) and Pd (PPh)₃)₄(2 mg, 0.002 mmol) in THF (2 mL) NaBH was added ₄(15 mg, 0.39 mmol). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was saturated with NH₄Aqueous Cl (1 mL) was quenched and concentrated under reduced pressure to give (A) as a brown solidS)-N-[(R) - (5-chloro-2-hydroxy-4-methylphenyl) [1- (6-oxo-1)H-pyridine-3-carbonyl) piperidin-4-yl]Methyl radical]-2-methylpropane-2-sulfinamide (90 mg, crude), which was used in the next step without further purification: c₂₃H₃₀ClN₃O₄S [M + H]⁺Calculated lcms (esi): 480, 482 (3: 1), found 480, 482 (3: 1).

Step c:

stirring at room temperature (S)-N-[(R) - (5-chloro-2-hydroxy-4-methylphenyl) [1- (6-oxo-1)H-pyridine-3-carbonyl) piperidin-4-yl]Methyl radical](iii) mixture of (2-methylpropane-2-sulfinamide (90 mg, 0.18 mmol) in 1, 4-dioxane (1 mL) aqueous HCl (4) was addedN,1 mL). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column, 30X 150 mm, 5 μm; mobile phase A: having a NH concentration of 10 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 10% B to 40% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.50 minutes. Collecting the fractions containing the desired product, concentrating under reduced pressure to obtain compound 228 (5- [4- [ (5- [)) as an off-white solid R) -amino (5-chloro-2-hydroxy-4-methylphenyl) methyl]Piperidine-1-carbonyl]-1H-pyridin-2-one) (38 mg, 53% two-step sum): C₁₉H₂₂ClN₃O₃ [M + H]⁺Calculated lcms (esi): 376, 378 (3: 1), measured 376, 378 (3: 1); ¹H NMR (400 MHz, CD₃OD) δ 7.68-7.56 (m, 2H), 7.10 (s, 1H), 6.69 (s, 1H), 6.55 (d, J = 9.2 Hz, 1H), 4.55-3.97 (m, 2H), 3.88 (d, J = 7.7 Hz, 1H), 3.11-2.79 (m, 2H), 2.27 (s, 3H), 2.07-1.93 (m, 2H), 1.52-1.40 (m, 1H), 1.39-1.16 (m, 2H)。

EXAMPLE 206 Compound 229 ((6)S)-6-[4-[(R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]Morpholine-3-one trifluoroacetic acid)

Step a:

stirring at room temperature (2)S) -3- [ (tert-butoxycarbonyl) amino group]-2-Hydroxypropionic acid (0.44 g, 2.14)To a solution of mmol) and HATU (0.81 g, 2.14 mmol) in DMF (5 mL) was added (bS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.60 g, 1.43 mmol) and Et₃N (0.43 g, 4.29 mmol). The resulting solution was stirred at room temperature for 1 hour. The reaction was purified by reverse phase chromatography eluting with 60% aqueous ACN (plus 0.05% TFA) to afford as a yellow oilN-[(2S)-3-[4-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidin-1-yl radical]-2-hydroxy-3-oxopropyl radical]Tert-butyl carbamate (0.54 g, 62%): C₂₇H₄₁Cl₂N₃O₆S [M + H]⁺Calculated lcms (esi): 606, 608 (3: 2), found 606, 608 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.22 (d, J = 13.9 Hz, 1H), 6.98 (s, 1H), 6.10-5.96 (m, 1H), 5.40 (dd, J = 19.7, 14.3 Hz, 2H), 4.67-4.50 (m, 3H), 4.50-4.37 (m, 2H), 4.03-3.88 (m, 1H), 3.48-3.34 (m, 1H), 3.17-2.88 (m, 2H), 2.63-2.50 (m, 1H), 2.20-2.12 (m, 1H), 2.04-1.93 (m, 1H), 1.64-1.54 (m, 1H), 1.48-1.39 (m, 11H), 1.17 (d, J = 4.8 Hz, 9H)。

step b:

at room temperature with stirring N-[(2S)-3-[4-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidin-1-yl]-2-hydroxy-3-oxopropyl radical]To a solution of tert-butyl carbamate (0.54 g, 0.89 mmol) in DCM (5 mL) was added TFA (1 mL). The resulting solution was stirred at room temperature for 0.5 hour. The reaction was quenched with saturated NaHCO₃The aqueous solution (20 mL) was neutralized to pH 7. The aqueous layer was extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to obtain (A) as a pale yellow oilS)-N-[(R)-[1-[(2S) -3-amino-2-hydroxypropionyl group]Piperidin-4-yl radical][4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]2-methylpropane-2-sulfinamide (0.43 g, crude), without further treatmentThe purification was used directly in the next step: c₂₂H₃₃Cl₂N₃O₄S [M + H]⁺Calculated lcms (esi): 506, 508 (3: 2), found 506, 508 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.26 (s, 1H), 7.00-6.90 (m, 1H), 6.10-5.96 (m, 1H), 5.47-5.33 (m, 2H), 4.97-4.72 (m, 1H), 4.65-4.45 (m, 3H), 4.45-4.23 (m, 1H), 4.20-3.91 (m, 2H), 3.20 (d, J = 45.5 Hz, 2H), 3.07-2.85 (m, 1H), 2.62-2.44 (m, 1H), 2.03-1.88 (m, 1H), 1.80-1.59 (m, 2H), 1.51-1.33 (m, 1H), 1.11 (d, J = 11.1 Hz, 9H)。

step c:

stirring in the downward direction at 0 ℃: (S)-N-[(R)-[1-[(2S) -3-amino-2-hydroxypropionyl group]Piperidin-4-yl radical][4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]2-methylpropane-2-sulfinamide (0.20 g, 0.39 mmol) and Et₃A solution of N (0.12 g, 1.18 mmol) in DCM (2 mL) was added chloroacetyl chloride (45 mg, 0.39 mmol) dropwise. The resulting mixture was stirred at 0 ℃ for 1 hour. The resulting mixture was diluted with water (30 mL) and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to obtain 2-chloro-propanoic acid as a yellow-green oilN-[(2S)-3-[4-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidin-1-yl radical]-2-hydroxy-3-oxopropyl radical]Acetamide (0.20 g, crude), which was used in the next step without further purification: c₂₄H₃₄Cl₃N₃O₅S [M + H]⁺Calculated lcms (esi): 582, 584, 586 (3: 3: 1), found 582, 584, 586 (3: 3: 1).

Step d:

stirring of 2-chloro-substituted benzene at room temperatureN-[(2S)-3-[4-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidin-1-yl radical]-2-hydroxy-3-oxopropyl radical]Acetamide (0.20 g, 0.34 mmol) and t-BuOK (77 mg, 0.68 mmol) in THF (2 mL). Mixing the obtained mixtureStirred at room temperature for 1 hour. The reaction mixture was diluted with water (30 mL) and extracted with EA (3X 20 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 50% aqueous ACN (plus 0.05% TFA) to give (a) as a pale yellow oilS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([1-[(2S) -5-oxomorpholine-2-carbonyl ]Piperidin-4-yl]) Methyl radical]2-methylpropane-2-sulfinamide (70 mg, 32% of two-step total): C₂₄H₃₃Cl₂N₃O₅S [M + H]⁺Calculated lcms (esi): 546, 548 (3: 2), found 546, 548 (3: 2);¹H NMR (400 MHz, CDCl₃)δ 7.22 (d, J = 9.2 Hz, 1H), 6.98 (s, 1H), 6.10-5.97 (m, 2H), 5.46-5.34 (m, 2H), 4.68-4.46 (m, 3H), 4.39 (t, J = 8.4 Hz, 1H), 4.35-4.28 (m, 1H), 4.27-4.18 (m, 1H), 4.09-3.99 (m, 1H), 3.99-3.83 (m, 1H), 3.82-3.62 (m, 1H), 3.52-3.40 (m, 1H), 3.05 (dt, J = 43.8, 12.5 Hz, 1H), 2.55 (dt, J = 40.6, 12.6 Hz, 1H), 2.28-2.17 (m, 1H), 2.05-1.96 (m, 1H), 1.74-1.51 (m, 2H), 1.46-1.34 (m, 1H), 1.21-1.10 (m, 9H)。

step e:

stirring at room temperature (S)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([1-[(2S) -5-oxomorpholine-2-carbonyl]Piperidin-4-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide (70 mg, 0.13 mmol) and Pd (PPh)₃)₄(1 mg, 0.001 mmol) in THF (1 mL) NaBH was added₄ (9 mg, 0.25 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The reaction was quenched with saturated NH at room temperature₄Aqueous Cl (1 mL) was quenched. Concentrating the obtained mixture under reduced pressure to obtain (A)S)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) ([1- [ (2)S) -5-oxomorpholine-2-carbonyl]Piperidin-4-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide (70 mg, crude), which was used in the next step without further purification: c₂₁H₂₉Cl₂N₃O₅S [M + H]⁺LCMS of (A), (B), (C)ESI) calculated values: 506, 508 (3: 2), found 506, 508 (3: 2).

Step f:

stirring at room temperature (S)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) ([1- [ (2)S) -5-oxomorpholine-2-carbonyl]Piperidin-4-yl radical]) Methyl radical](iii) mixture of (E) -2-methylpropane-2-sulfinamide (70 mg, 0.14 mmol) in 1, 4-dioxane (1 mL) aqueous HCl (4) was added N,1 mL). The resulting mixture was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xselect CSH OBD column 30 × 150 mm 5 μm, n; a mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 5% B to 25% B in 7 minutes; a detector: UV 220/254 nm; retention time: 6.55 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure to give compound 229 ((6) as an off-white solidS)-6-[4-[(R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]Morpholin-3-one trifluoroacetic acid) (10 mg, 15% two-step sum): C₁₇H₂₁Cl₂N₃O₄[M + H]⁺Calculated lcms (esi): 402, 404 (3: 2), measured 402, 404 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.43 (s, 1H), 7.09 (s, 1H), 4.72-4.36 (m, 2H), 4.33-4.24 (m, 1H), 4.24-3.99 (m, 3H), 3.76-3.58 (m, 1H), 3.43-3.36 (m, 1H), 3.18-3.04 (m, 1H), 2.68 (dt, J = 57.8, 12.8 Hz, 1H), 2.48-2.28 (m, 1H), 2.09-1.97 (m, 1H), 1.52-1.00 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.08。

EXAMPLE 207 Compound 231 (6- [4- [ (()R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]Morpholine-3-one)

Step a:

to a stirred 3- [ (tert-butoxycarbonyl) amino group at room temperature]-solution of 2-hydroxypropionic acid (0.59 g, 2.88 mmol) and HATU (1.09 g, 2.87 mmol) in DMF (10 mL)Adding into the solution (S)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (1.00 g, 2.38 mmol) and Et ₃N (0.72 g, 7.15 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction was purified by reverse phase chromatography eluting with 60% aqueous ACN (plus 0.05% TFA) to afford as a pale yellow oilN-(3-[4-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidin-1-yl radical]-2-hydroxy-3-oxopropyl) carbamic acid tert-butyl ester (0.80 g, 44%): C₂₇H₄₁Cl₂N₃O₆S [M + H]⁺Calculated lcms (esi): 606, 608 (3: 2), found 606, 608 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.26-7.18 (m, 1H), 6.98 (s, 1H), 6.11-5.96 (m, 1H), 5.47-5.32 (m, 2H), 4.71-4.50 (m, 2H), 4.50-4.37 (m, 2H), 4.06-3.77 (m, 3H), 3.48-3.34 (m, 1H), 3.19-2.90 (m, 2H), 2.66-2.50 (m, 1H), 2.21-1.96 (m, 1H), 1.63-1.48 (m, 2H), 1.48-1.41 (m, 10H), 1.19-1.15 (m, 9H)。

step b:

at room temperature with stirringN-(3-[4-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidin-1-yl radical]To a solution of tert-butyl (2-hydroxy-3-oxopropyl) carbamate (0.80 g, 1.32 mmol) in DCM (8 mL) was added TFA (2 mL). The resulting solution was stirred at room temperature for 30 minutes. The reaction was performed with saturated NaHCO at 0 deg.C₃The aqueous solution (20 mL) was neutralized to pH 7. The resulting mixture was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give (a) as a pale yellow solidS)-N-[(R) - [1- (3-amino-2-hydroxypropionyl) piperidin-4-yl group][4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ]Methyl radical]2-methylpropane-2-sulfinamide (0.7 g, crude), which was used in the next step without further purification: c₂₃H₃₃Cl₂N₃O₄S [M + H]⁺LCMS (ESI) calculated value of (A): 506, 508 (3: 2), measured 506, 508 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.22 (s, 1H), 6.98 (s, 1H), 6.09-5.96 (m, 1H), 5.45-5.32 (m, 2H), 4.68-4.23 (m, 5H), 4.12-3.84 (m, 1H), 3.38-3.07 (m, 2H), 3.07-2.90 (m, 1H), 2.64-2.41 (m, 1H), 2.09-1.96 (m, 2H), 1.59-1.20 (m, 3H), 1.13 (d, J = 8.3 Hz, 9H)。

step c:

stirring in the downward direction at 0 ℃: (S)-N-[(R) - [1- (3-amino-2-hydroxypropionyl) piperidin-4-yl group][4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]2-methylpropane-2-sulfinamide (0.70 g, 1.38 mmol) and Et₃A solution of N (0.42 g, 4.15 mmol) in DCM (10 mL) was added chloroacetyl chloride (0.16 g, 1.38 mmol) dropwise. The resulting mixture was stirred at 0 ℃ for 1 hour. The resulting mixture was diluted with water (20 mL) and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to obtain 2-chloro-substituted benzene as a pale yellow oilN-(3-[4-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidin-1-yl radical]-2-hydroxy-3-oxopropyl) acetamide (0.7 g, crude), which was used in the next step without further purification: c₂₄H₃₄Cl₃N₃O₅S [M + H]⁺Calculated lcms (esi): 582, 584, 586 (3: 3: 1), found 582, 584, 586 (3: 3: 1).

Step d:

2-chloro- N-(3-[4-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidin-1-yl radical]-2-hydroxy-3-oxopropyl) acetamide (0.70 g, 1.20 mmol) andta mixture of BuOK (0.27 g, 2.40 mmol) in THF (70 mL) was stirred at room temperature for 1 h. The resulting mixture was diluted with water (100 mL) and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography using 60% ACN in water (0.0% added)5% TFA) to give (A) as a pale yellow oilS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (5-Oxomorpholine-2-carbonyl) piperidin-4-yl]Methyl radical]2-methylpropane-2-sulfinamide (0.14 g, 19% of the total of the three steps): C₂₄H₃₃Cl₂N₃O₅S [M + H]⁺Calculated lcms (esi): 546, 548 (3: 2), found 546, 548 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.26-7.17 (m, 1H), 6.99 (s, 1H), 6.48-6.33 (m, 1H), 6.10-5.94 (m, 1H), 5.48-5.34 (m, 2H), 4.68-4.49 (m, 3H), 4.47-4.19 (m, 3H), 4.10-3.97 (m, 1H), 3.97-3.82 (m, 2H), 3.52-3.41 (m, 1H), 3.17-2.87 (m, 1H), 2.64-2.44 (m, 1H), 2.28-1.91 (m, 2H), 1.62-1.24 (m, 3H), 1.19-1.14 (m, 9H)。

step e:

stirring at room temperature (S)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (5-Oxomorpholine-2-carbonyl) piperidin-4-yl]Methyl radical]-2-methylpropane-2-sulfinamide (0.10 g, 0.18 mmol) and Pd (PPh)₃)₄(4 mg, 0.004 mmol) in THF (4 mL) NaBH was added₄(28 mg, 0.73 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The resulting mixture was washed with saturated NH ₄Aqueous Cl solution (1 mL) was quenched and concentrated under reduced pressure to give (A), (B)S)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) [1- (5-oxomorpholine-2-carbonyl) piperidin-4-yl group]Methyl radical]2-methylpropane-2-sulfinamide (0.20 g, crude), which was used in the next step without further purification: c₂₁H₂₉Cl₂N₃O₅S [M + H]⁺Calculated lcms (esi): 506, 508 (3: 2), found 506, 508 (3: 2).

Step f:

stirring at room temperature (S)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) [1- (5-oxomorpholine-2-carbonyl) piperidin-4-yl group]Methyl radical]To a mixture of (E) -2-methylpropane-2-sulfinamide (0.10 g, 0.20 mmol) in 1, 4-dioxane (1 mL) was added aqueous HCl (4)N1 mL). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. Removing residuesPurification by preparative HPLC was carried out under the following conditions: column: xbridge Shield RP18 OBD column, 30X 150 mm, 5 μm; mobile phase A: having a NH concentration of 10 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 15% B to 40% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.50 minutes. Collecting the fractions containing the desired product, concentrating under reduced pressure to obtain compound 231 (6- [4- [ (R))R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group ]Piperidine-1-carbonyl]Morpholin-3-one) (7.5 mg, 10% of the two steps in total): C₁₇H₂₁Cl₂N₃O₄ [M + H]⁺Lcms (esi) calculated value of (a): 402, 404 (3: 2), measured 402, 404 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.23 (d, J = 5.6 Hz, 1H), 6.88 (s, 1H), 4.70-4.43 (m, 2H), 4.34-3.98 (m, 2H), 3.98-3.76 (m, 1H), 3.69-3.57 (m, 1H), 3.45-3.34 (m, 1H), 3.21-2.89 (m, 1H), 2.78-2.50 (m, 1H), 2.28-1.65 (m, 3H), 1.60-1.40 (m, 1H), 1.40-1.02 (m, 2H)。

example 208 Compound 236 (2- [ (2- [))R) -amino [1- (pyrrolidine-3-sulfonyl) piperidin-4-yl]Methyl radical]-4-chloro-5-methylphenol trifluoroacetic acid)

Step a:

stirring in the downward direction at 0 ℃: (S)-N-[(R) - [ 5-chloro-4-methyl-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide (0.20 g, 0.50 mmol) and Et₃To a solution of N (0.15 g, 1.50 mmol) in DCM (3 mL) was added tert-butyl 3- (chlorosulfonyl) pyrrolidine-1-carboxylate (0.16 g, 0.60 mmol). The resulting mixture was stirred at 0 ℃ for 1 hour. The reaction was quenched with water (20 mL) at room temperature and extracted with EA (3X 20 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. Filtering, concentrating the filtrate under reduced pressure to obtain 3- [4- [ (R) ((R))R) - [ 5-chloro-4-methyl-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropaneAlk-2-sulfinyl]Amino group]) Methyl radical]Piperidin-1-ylsulfonyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (0.25 g, crude), which was used in the next step without further purification: c₂₉H₄₆ClN₃O₆S₂ [M + H]⁺Calculated lcms (esi): 632, 634 (3: 1), found 632, 634 (3: 1); ¹H NMR (400 MHz, CD₃Cl) δ 7.07 (s, 1H), 6.75 (s, 1H), 6.15-5.89 (m, 1H), 5.46-5.29 (m, 2H), 4.65-4.47 (m, 2H), 4.42-4.23 (m, 1H), 4.04-3.75 (m, 2H), 3.75-3.52 (m, 4H), 3.48-3.32 (m, 1H), 2.90-2.59 (m, 2H), 2.36 (s, 3H), 2.30-2.14 (m, 2H), 2.02-1.67 (m, 2H), 1.53-1.40 (m, 10H), 1.40-1.20 (m, 2H), 1.14 (s, 9H)。

Step b:

to stirred 3- [4- [ (v) () ] at room temperatureR) - [ 5-chloro-4-methyl-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidin-1-ylsulfonyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (0.25 g, 0.40 mmol) and Pd (PPh)₃)₄(5 mg, 0.004 mmol) in THF (3 mL) NaBH was added₄(30 mg, 0.79 mmol). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was washed with saturated NH₄Aqueous Cl (1 mL) was quenched and concentrated under reduced pressure to give 3- [4- [ (R) as a brown solidR) - (5-chloro-2-hydroxy-4-methylphenyl) ([ ((ii) ((iii))S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidin-1-ylsulfonyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (0.25 g, crude), which was used in the next step without further purification: c₂₆H₄₂ClN₃O₆S₂ [M + H]⁺Calculated lcms (esi): 592, 594 (3: 1), found 592, 594 (3: 1).

Step c:

stirring 3- [4- [ (ii) at room temperatureR) - (5-chloro-2-hydroxy-4-methylphenyl) ([ ((ii) ((iii))S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidin-1-ylsulfonyl radical]To a mixture of pyrrolidine-1-carboxylic acid tert-butyl ester (0.25 g, 0.42 mmol) in 1, 4-dioxane (1 mL) was added aqueous HCl (4N1 mL). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. Removing residues The residue was purified by preparative HPLC under the following conditions: column: xselect CSH OBD column 30X 150 mm 5 μm; a mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 7% B to 18% B in 7 minutes; a detector: UV 220/254 nm; retention time: 6.92 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure to give compound 236 (2- [ (2-)) as an off-white solidR) -amino [1- (pyrrolidine-3-sulfonyl) piperidin-4-yl]Methyl radical]-4-chloro-5-methylphenol trifluoroacetic acid) (81 mg, 32% of the total of the three steps): C₁₇H₂₆ClN₃O₃S [M + H]⁺Calculated lcms (esi): 388, 390 (3: 1), found 388, 390 (3: 1); ¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 6.86 (s, 1H), 4.21-4.02 (m, 2H), 3.94 (d, J = 13.1 Hz, 1H), 3.79 (d, J = 12.9 Hz, 1H), 3.72-3.58 (m, 2H), 3.55-3.46 (m, 1H), 3.44-3.35 (m, 1H), 3.05-2.94 (m, 1H), 2.94-2.82 (m, 1H), 2.48-2.35 (m, 2H), 2.35-2.21 (m, 4H), 2.08-1.99 (m, 1H), 1.52-1.37 (m, 2H), 1.37-1.23 (m, 1H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.17。

example 209 Compound 240 (2- [ (2- [))R) -amino (1- [ imidazo [1, 2-)a]Pyrimidine-6-carbonyl]Piperidin-4-yl) methyl]-4-chloro-5-methylphenol trifluoroacetic acid)

Step a:

to stirred imidazo [1,2 ] s at room temperature-a]To a solution of pyrimidine-6-carboxylic acid (0.12 g, 0.75 mmol) and HATU (0.29 g, 0.75 mmol) in DMF (2 mL) was added: (S)-N-[(R) - [ 5-chloro-4-methyl-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide (0.20 g, 0.50 mmol) and Et₃N (0.15 g, 1.50 mmol). The reaction was stirred at room temperature for 0.5 h. The resulting mixture was diluted with EA (20 mL) and water (20 mL). The aqueous solution was extracted with EA (3X 20 mL). The combined organic layers were washed with brine (5X 20 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtrationThe filtrate was concentrated under reduced pressure to give (A) as a yellow foamS)-N-[(R) - [ 5-chloro-4-methyl-2- (prop-2-en-1-yloxy) phenyl](1- [ imidazo [ 2 ] ] [ ]1,2-a]Pyrimidine-6-carbonyl]Piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.30 g, crude), which was used in the next step without further purification: c₂₇H₃₄ClN₅O₃S [M + H]⁺Calculated lcms (esi): 544, 546 (3: 1), found 544, 546 (3: 1);¹H NMR (400 MHz, CDCl₃) δ 8.72 (d, J = 2.4 Hz, 1H), 8.59 (s, 1H), 7.91 (s, 1H), 7.66 (s, 1H), 7.09 (s, 1H), 6.77 (s, 1H), 6.12-5.99 (m, 1H), 5.48-5.28 (m, 2H), 4.68-4.49 (m, 2H), 4.42-4.27 (m, 1H), 4.10-3.97 (m, 2H), 3.14-2.97 (m, 1H), 2.45-2.25 (m, 4H), 2.21 (d, J = 13.1 Hz, 1H), 2.14-2.08 (m, 1H), 1.59-1.42 (m, 1H), 1.42-1.31 (m, 2H), 1.14 (s, 9H)。

step b:

stirring at room temperature (S)-N-[(R) - [ 5-chloro-4-methyl-2- (prop-2-en-1-yloxy) phenyl](1- [ imidazo [1,2 ]-a]Pyrimidine-6-carbonyl]Piperidin-4-yl) methyl](iii) -2-methylpropane-2-sulfinamide (0.15 g, 0.28 mmol) in HOAc (3 mL) Pd (PPh) was added₃)₄(0.16 g, 0.14 mmol). The reaction was stirred at room temperature for 16 hours. The reaction was concentrated under reduced pressure to give (A) as a yellow solidS)-N-[(R) - (5-chloro-2-hydroxy-4-methylphenyl) (1- [ imidazo [1,2 ]-a]Pyrimidine-6-carbonyl]Piperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide (150 mg, crude), which was used in the next step without further purification: c₂₄H₃₀ClN₅O₃S [M + H]⁺Calculated lcms (esi): 504, 506 (3: 1), found 504, 506 (3: 1).

Step c:

stirring at room temperature (S)-N-[(R) - (5-chloro-2-hydroxy-4-methylphenyl) (1- [ imidazo [1,2 ] -a]Pyrimidine-6-carbonyl]Piperidin-4-yl) methyl](iii) solution of (E) -2-methylpropane-2-sulfinamide (0.15 g, 0.30 mmol) in 1, 4-dioxane (3 mL) was added aqueous HCl (4)N1 mL). Will react inStir at room temperature for 1 hour. The reaction was diluted with EA (20 mL) and water (10 mL). The organic layer was washed with aqueous HCl (1)N2X 20 mL). The combined aqueous solutions were concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Prep C18 OBD column, 5 μm, 19X 150 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 3% B to 29% B in 7 minutes; a detector: UV 254/220 nm; retention time: 5.32 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure, and yielded compound 240 (2- [ ((2) as a pale yellow solidR) -amino (1- [ imidazo [1, 2-)a]Pyrimidine-6-carbonyl]Piperidin-4-yl) methyl]-4-chloro-5-methylphenol trifluoroacetic acid) (75 mg, 58% of a three-step total): C₂₀H₂₂ClN₅O₂[M + H]⁺Calculated lcms (esi): 400, 402 (3: 1), found 400, 402;¹H NMR (400 MHz, DMSO-d ₆) δ 9.30 (s, 1H), 8.81 (d, J = 2.1 Hz, 1H), 8.09 (dd, J = 11.9, 2.0 Hz, 2H), 7.36 (s, 1H), 6.87 (s, 1H), 4.62-4.31(m, 1 H), 4.28-4.12 (m, 1H), 4.09-3.55 (m, 1H), 3.27-2.65 (m, 2H), 2.31-2.10 (m, 4H), 2.12-1.76 (m, 1H), 1.48-1.00 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.22.

in a manner analogous to that described for compound 240, fromS)-N-[(R) - [ 5-chloro-4-methyl-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]Starting with 2-methylpropane-2-sulfinamide and the corresponding acid (which is prepared as described herein, or is available from a commercial source), the compounds in table 1e below are prepared.

TABLE 1e

Example 210 Compound 244 ((2)R)-1-[4-[(R) -amino (3-chloro-2-fluoro-6-hydroxy-4-methylphenyl) methyl]Piperidin-1-yl]-2, 3-dihydroxypropan-1-one)

A, step a:

under nitrogen atmosphere, at-65 ℃ for 15 minutesi-Pr₂A solution of NH (8.98 g, 88.73 mmol) in THF (70 mL) was added dropwisenBuLi (25.4 mL, 63.53 mmol, 2.5M in hexane). After stirring for 45 minutes, the reaction solution was cooled to-85 ℃. Then 4-chloro-3-fluoro-5-methylphenyl is added dropwise at-85 ℃ for 0.5 hour under nitrogen atmosphereN,NA solution of diethyl carbamate (intermediate 73, example 73) (15.00 g, 57.76 mmol) in THF (90 mL). Stirring at-85 deg.C for 40 min under nitrogen atmosphere, and adding 4- [ [ (C) in drops at-80 deg.C for 0.5 hrS) -2-methylpropan-2-sulfinyl]Imino radical]Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester (22.00 g, 69.52 mmol) in THF (90 mL). The resulting mixture was stirred at-65 ℃ for 1 hour. The reaction was quenched with saturated NH at-65 deg.C₄Aqueous Cl (50 mL) was quenched and diluted with brine (100 mL). The resulting mixture was extracted with EA (3X 100 mL). The combined organic layers were washed with brine (2X 50 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography, eluting with PE/EA (1/3), and obtaining 4- [ (R) ((R)) as an off-white foam R) - [ 3-chloro-6- [ (diethylcarbamoyl) oxy ] carbonyl]-2-fluoro-4-methylphenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester (25 g, 75%) C₂₇H₄₃ClFN₃O₅S [M + H]⁺Calculated lcms (esi): 576, 578 (3: 1), found 576, 578 (3: 1);¹H NMR (400 MHz, CDCl₃) δ 6.87 (s, 1H), 4.53-3.72 (m, 4H), 3.56-3.25 (m, 4H), 2.75 (s, 3H), 2.63 (d, J = 41.6 Hz, 2H), 2.26 (dd, J = 27.8, 17.3 Hz, 1H), 1.96 (s, 1H), 1.47 (d, J = 2.5 Hz, 9H), 1.34-1.17 (m, 9H), 1.10 (s, 9H)； ¹⁹F NMR (376 MHz, CDCl₃) δ -115.04.

step b:

at room temperature to 4- [ ()R) - [ 3-chloro-6- [ (diethylcarbamoyl) oxy ] carbonyl]-2-fluoro-4-methylphenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]To a solution of tert-butyl piperidine-1-carboxylate (25.00 g, 43.39 mmol) in MeOH (350 mL) was added NaOH (8.68 g, 216.95 mmol). The reaction mixture was stirred at 50 ℃ for 3 hours. After cooling to room temperature, the resulting mixture was taken up in aqueous HCl (1)N) Acidified to pH 7 and extracted with DCM (3X 100 mL). The combined organic layers were washed with brine (2X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 4- [ ((R))R) - (3-chloro-2-fluoro-6-hydroxy-4-methylphenyl) ([ ((ii) ((iii))S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester (20 g, crude): C₂₂H₃₄ClFN₂O₄S [M + H]⁺Calculated lcms (esi): 477, 479 (3: 1), found 477, 479 (3: 1).

Step c:

4- [ (at 0 deg.C)R) - (3-chloro-2-fluoro-6-hydroxy-4-methylphenyl) ([ ((ii) ((iii)) S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]To a solution of tert-butyl piperidine-1-carboxylate (20.00 g, 41.93 mmol) in DCM (160 mL) was added TFA (40 mL). The reaction mixture was allowed to warm to room temperature and stirred for 1.5 hours. The resulting solution was saturated with Na₂CO₃The aqueous solution was neutralized to pH 8 at 0 ℃ and extracted with DCM (8X 60 mL). Combining the combined organic layers over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give (a) as a pale yellow solidS)-N-[(R) - (3-chloro-2-fluoro-6-hydroxy-4-methylphenyl) (piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (20.00 g, 88%): C₁₇H₂₆ClFN₂O₂S [M + H]⁺Calculated lcms (esi): 377, 379 (3: 1), found 377, 379 (3: 1).

Step d:

to stirred HATU (1.66 g, 4.38 mmol) and (4) at room temperatureR) Et was added to a solution of (0.51 g, 3.50 mmol) of (E) -2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid in DMF (10 mL)₃N (0.89 g, 8.76 mmol) and (C)S)-N-[(R) - (3-chloro-2-fluoro-6-hydroxy-4-methylphenyl) (piperidin-4-yl) methyl]-solution of 2-methylpropane-2-sulfinamide (1.10 g, 2.92 mmol) in DMF (5 mL). The reaction solution was stirred at room temperature for 1 hour. The resulting solution was quenched with water (80 mL) and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (5X 50 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to obtain (A) as a pale yellow oilS)-N-[(R) - (3-chloro-2-fluoro-6-hydroxy-4-methylphenyl) ([1- [ (2)R) -2, 3-dihydroxypropanoyl group]Piperidin-4-yl radical]) Methyl radical]2-methylpropane-2-sulfinamide (1.5 g, crude): C₂₃H₃₄ClFN₂O₅S [M + H]⁺505, 507 (3: 1), found 505, 507 (3: 1).

Step e:

at 0 deg.C toS)-N-[(R) - (3-chloro-2-fluoro-6-hydroxy-4-methylbenzeneRadical) ([1- [ (4)R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide (1.50 g, 2.97 mmol) in THF (15 mL) aqueous HCl (4) was addedN5 mL). The reaction solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure. The residue was purified under the following conditions: column: XSelect CSH Prep C18 OBD column, 5 μm, 19X 150 mm; mobile phase A: having a NH concentration of 10 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 15% B to 20% B in 6 minutes; 210 nm; a detector: UV 254 nm; retention time: 5.02 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to afford compound 244 ((2) as an off-white solidR)-1-[4-[(R) -amino (3-chloro-2-fluoro-6-hydroxy-4-methylphenyl) methyl]Piperidin-1-yl radical ]-2, 3-dihydroxypropan-1-one) (296 mg, 28% of two steps in total): C₁₆H₂₂ClFN₂O₄ [M + H]⁺Lcms (esi) calculated value of (a): 361, 363 (3: 1), found 361, 363 (3: 1);¹H NMR (400 MHz, CD₃OD) δ 6.52 (s, 1H), 4.67-4.44 (m, 2H), 4.13 (dd, J =48.6, 10.5 hr z, 2H), 3.73-3.62 (m, 2H), 3.12-3.01 (m, 1H), 2.74-2.54 (m, 1H), 2.29 (s, 3H), 2.13-2.04 (m, 2H), 1.55-1.51 (m, 1H), 1.40-1.15 (m, 2H);¹⁹F NMR (376 MHz, CDCl₃) δ -119.35。

EXAMPLE 211 Compound 251 (5- [4- [ (S))R) -amino (5-chloro-2-hydroxy-4-methylphenyl) methyl]Piperidine-1-carbonyl]-3-methoxy-1_H-pyridin-2-one trifluoroacetic acid

Step a:

to stirred 5-methoxy-6-oxo-1 at room temperatureH(0.19 g, 0.94 mmol) of pyridine-3-carboxylic acid, EDCI (0.18 g, 0.94 mmol) and HOBt (0.13 g, 0.94 mmol) in DMF (3 mL) was addedS)-N-[(R) - [ 5-chloro-4-methyl-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide (0)25 g, 0.63 mmol) and Et₃N (0.19 g, 1.88 mmol). The reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was quenched with water (20 mL) and extracted with EA (3X 20 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give (A) in the form of a yellow semisolidS)-N-[(R) - [ 5-chloro-4-methyl-2- (prop-2-en-1-yloxy) phenyl ][1- (5-methoxy-6-oxo-1)H-pyridine-3-carbonyl) piperidin-4-yl]Methyl radical]2-methylpropane-2-sulfinamide (0.25 g, crude): C₂₇H₃₆ClN₃O₅S [M + H]⁺Calculated lcms (esi): 550, 552 (3: 1), found 550, 552 (3: 1).

Step b:

stirring under nitrogen atmosphere at room temperatureS)-N-[(R) - [ 5-chloro-4-methyl-2- (prop-2-en-1-yloxy) phenyl][1- (5-methoxy-6-oxo-1)H-pyridine-3-carbonyl) piperidin-4-yl]Methyl radical](ii) -2-methylpropane-2-sulfinamide (0.25 g, crude) to a mixture in HOAc (2 mL) Pd (PPh) was added₃)₄(0.21 g, 0.18 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. Concentrating the obtained mixture under reduced pressure to obtain (A) in the form of yellow oilS)-N-[(R) - (5-chloro-2-hydroxy-4-methylphenyl) [1- (5-methoxy-6-oxo-1H-pyridine-3-carbonyl) piperidin-4-yl]Methyl radical]2-methylpropane-2-sulfinamide (0.20 g, crude): C₂₄H₃₂ClN₃O₅S [M + H]⁺Calculated lcms (esi): 510, 512 (3: 1), found 510, 512 (3: 1).

Step c:

stirring at room temperature under air atmosphere (S)-N-[(R) - (5-chloro-2-hydroxy-4-methylphenyl) [1- (5-methoxy-6-oxo-1H-pyridine-3-carbonyl) piperidin-4-yl]Methyl radical]-2-methylpropane-2-sulfinamide (0.20 g, crude) to a mixture in THF (2 mL) was added aqueous HCl (4) N0.5 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions:column: xbridge Prep C18 OBD column 19X 150 mm, 5 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 5% B to 27% B in 7 minutes; a detector: UV 254/220 nm; retention time: 7.07 min. Collecting the fractions containing the desired product, concentrating under reduced pressure to obtain compound 251 (5- [4- [ (R))R) -amino (5-chloro-2-hydroxy-4-methylphenyl) methyl]Piperidine-1-carbonyl]-3-methoxy-1_H-pyridin-2-one trifluoroacetic acid) (118 mg, 73% of the total of the three steps) C₂₀H₂₄ClN₃O₄ [M + H]⁺Calculated lcms (esi): 406, 408 (3: 1), found 406, 408 (3: 1); ¹H NMR (400 MHz, CD₃OD) δ 7.28-7.19 (m, 2H), 6.95 (d, J = 2.2 Hz, 1H), 6.85 (s, 1H), 4.57-4.00 (m, 3H), 3.86 (s, 3H), 3.21-2.86 (m, 2H), 2.52-2.36 (m, 1H), 2.31 (s, 3H), 2.08-2.00 (m, 1H), 1.51-1.32 (m, 2H), 1.31-1.13 (m, 1H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.18.

in a manner analogous to that described for compound 251, fromS)-N-[(R) - [ 5-chloro-4-methyl-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]Starting with 2-methylpropane-2-sulfinamide and the corresponding acid or acid salt (which is prepared as described herein, or is available from a commercial source), the compounds of table 1f below are prepared.

The acid salt used to prepare compound 207, i.e., lithium 5- (hydroxymethyl) -6-oxo-1, 6-dihydropyridine-3-carboxylate, was prepared as follows.

Step a':

to a stirred solution of methyl 5-bromo-2-hydroxy-1, 2-dihydropyridine-3-carboxylate (2.00 g, 8.55 mmol) in THF (20 mL) and MeOH (1.00 mL) under a nitrogen atmosphere at 0 deg.C was added LiBH₄(8.55 mL, 17.09 mmol, 2M in THF), the resulting mixture was stirred at room temperature for 3 hours. The reaction was then quenched with water (10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and DCMMeOH (10/1) to give 5-bromo-3- (hydroxymethyl) -1 as an off-white solidH-pyridin-2-one (1.00g, 57%): C₆H₆BrNO₂ [M + H]⁺Calculated lcms (esi): 204, 206 (1: 1) found: 204, 206 (1: 1);¹H NMR (400 MHz, DMSO-d ₆ ) δ 6.90-6.82 (m, 1H), 6.72-6.68 (m, 1H), 3.68 (s, 3H)。

step b':

to stirred 5-bromo-3- (hydroxymethyl) -1 at room temperatureHPyridin-2-one (0.50 g, 2.45 mmol) and Pd (dppf) Cl₂ CH₂Cl₂To a solution of the adduct (0.20 g, 0.25 mmol) in MeOH (5 mL) was added TEA (0.50 g, 4.90 mmol). The resulting mixture was stirred at 100 ℃ overnight under an atmosphere of CO (5 atm), and then concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/MeOH 20/1) to give 5- (hydroxymethyl) -6-oxo-1 as a pale pink solidH-pyridine-3-carboxylic acid methyl ester (60 mg, 13%): C₈H₉NO₄ [M + H]⁺Calculated lcms (esi): 184 measured value: 184.

step c':

Reacting 5- (hydroxymethyl) -6-oxo-1H-pyridine-3-carboxylic acid methyl ester (60 mg, 0.33 mmol) and LiOH.H₂O (27 mg, 0.66 mmol) in MeOH (1 mL) and H₂A solution in O (0.25 mL) was stirred at 40 ℃ for 1 hour. The resulting mixture was concentrated under reduced pressure to give lithium 5- (hydroxymethyl) -6-oxo-1, 6-dihydropyridine-3-carboxylate (70 mg, crude) as an off-white solid, which was used in the next step without further purification: c₇H₇NO₄ [M + H]⁺Calculated lcms (esi): 170, found value 170.

TABLE 1f

Example 212 compoundingSubstance 257 (5- [4- [ (()R) -amino (3, 4-dichloro-2-fluoro-6-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]-1H-pyridin-2-one trifluoroacetic acid

Step a:

to stirred 6-oxo-1 at room temperatureH-pyridine-3-carboxylic acid (84 mg, 0.60 mmol), EDCI (0.12 g, 0.60 mmol) and HOBt (82 mg, 0.60 mmol) in DMF (4 mL) were added portionwise: (R)-N-[(S) - (3, 4-dichloro-2-fluoro-6-hydroxyphenyl) (piperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide (intermediate 18, example 18) (0.20 g, 0.50 mmol) and Et₃N (0.15 g, 1.51 mmol). After stirring at room temperature for 2 hours, the reaction solution was quenched with water (20 mL) at room temperature and extracted with EA (2X 50 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give (A)S)-N-((R) - (3, 4-dichloro-2-fluoro-6-hydroxyphenyl) (1- (6-oxo-1, 6-dihydropyridine-3-carbonyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide. The crude product was used without further purification in the subsequent step: c₂₂H₂₆Cl₂FN₃O₄S [M + H]⁺Lcms (esi) calculated value of (a): 518, 520 (3: 2), found 518, 520 (3: 2).

Step b:

stirring at room temperature (S)-N-((R) - (3, 4-dichloro-2-fluoro-6-hydroxyphenyl) (1- (6-oxo-1, 6-dihydropyridine-3-carbonyl) piperidin-4-yl) methyl) -2-methylpropane-2-sulfinamide (crude) to a mixture in THF (4 mL) aqueous HCl (6 mL) was added dropwiseN2 mL). The reaction solution was stirred at room temperature for 2 hours. The reaction solution was stirred at room temperature for 1 hour. The resulting solution was diluted with EA (10 mL). The organic layer was washed with aqueous HCl (1)N3X 10 mL). The combined aqueous layers were washed with EA (3X 10 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xselect CSH OBD column 30 × 150 mm, 5 μm; flow ofPhase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 5% B to 28% B in 7 minutes; a detector: UV 220 nm; retention time: 6.43 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure to give compound 257 (5- [4- [ (R)) R) -amino (3, 4-dichloro-2-fluoro-6-hydroxyphenyl) methyl]Piperidine-1-carbonyl]-1H-pyridin-2-one trifluoroacetic acid) (64 mg, 59% of two steps in total): C₁₈H₁₈Cl₂FN₃O₃ [M + H]⁺Lcms (esi) calculated value of (a): 414, 416 (3: 2), found 414, 416 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.72-7.56 (m, 2H), 6.98 (d, J = 1.8 Hz, 1H), 6.56 (d, J = 9.4 Hz, 1H), 4.43 (d, J = 10.0 Hz, 1H), 4.38-4.06 (m, 2H), 3.15-2.88 (m, 2H), 2.62-2.39 (m, 1H), 2.12-1.93 (m, 1H), 1.55-1.15 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.29, -113.13.

example 213 Compound 260 ((2)R,3S)-2-[4-[(R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]Oxetane-3-ol trifluoroacetic acid

Step a:

stirring at room temperature (2R,3S) (1) - (3-benzoyloxy) oxolane-2-carboxylic acid (0.13 g, 0.54 mmol) and HATU (0.20 g, 0.54 mmol) in DMF (3 mL) was addedS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.15 g, 0.34 mmol) and Et₃N (0.11 g, 1.07 mmol). The reaction was stirred at room temperature for 0.5 h. The reaction was purified by reverse phase chromatography using a column having 10 mmoL/L NH₄HCO₃Eluted with 55% ACN in water to give (A) as a pale yellow solid2R, 3S)-2-[4-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidine-1-carbonyl]Oxetan-3-ylBenzoate (0.15 g, 57%): C₃₁H₃₈Cl₂N₂O₆S [M + H]⁺Calculated lcms (esi): 637, 639 (3: 2), found 637, 639 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.98 (t, J = 9.6 Hz, 2H), 7.67-7.56 (m, 1H), 7.51-7.37 (m, 2H), 7.25-7.17 (m, 1H), 6.97-6.86 (m, 1H), 6.07-5.92 (m, 1H), 5.88 (t, J =6.1 Hz, 1H), 5.41-5.28 (m, 2H), 4.92 (t, J = 5.6 Hz, 1H), 4.74-4.39 (m, 4H), 4.39-4.25 (m, 2H), 4.07-3.94 (m, 2H), 3.82-3.61 (m, 1H), 2.86 (dt, J = 94.8, 12.5 Hz, 1H), 2.47-2.30 (m, 2H), 2.30-2.14 (m, 1H), 1.97-1.80 (m, 1H), 1.67-1.52 (m, 2H), 1.13 (d, J = 24.7 Hz, 9H)。

step b:

Stirring at room temperature (2R,3S)-2-[4-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidine-1-carbonyl]Oxetane-3-benzoic acid ester (0.15 g, 0.24 mmol) and Pd (PPh)₃)₄(5 mg, 0.01 mmol) in THF (3 mL) NaBH was added₄(18 mg, 0.47 mmol). The reaction was stirred at room temperature for 1 hour. Reacting with saturated NH₄Aqueous Cl (0.5 mL) was quenched and concentrated under reduced pressure to give (as a brown oil) ((R))2R,3S)-2-[4-[(R) - (4, 5-dichloro-2-hydroxyphenyl) ([ ((ii) ((iii))S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidine-1-carbonyl]Oxetane-3-benzoate (0.15 g, crude), which was used in the next step without further purification: c₂₈H₃₄Cl₂N₂O₆S [M + H]⁺Calculated lcms (esi): 597, 599 (3: 2), found 597, 599 (3: 2).

Step c:

stirring at room temperature (2R,3S)-2-[4-[(R) - (4, 5-dichloro-2-hydroxyphenyl) ([ ((ii) ((iii))S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidine-1-carbonyl]To a solution of oxacyclopentane-3-benzoate (0.15 g, 0.25 mmol) in THF (3 mL) was added aqueous HCl (4)N2 mL). The reaction was stirred at room temperature for 1 hour. The reaction is concentrated under reduced pressureObtained in the form of a brown solid (2R,3S)-2-[4-[(R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group ]Piperidine-1-carbonyl]Oxetane-3-benzoate (0.15 g, crude), which was used in the next step without further purification: c₂₄H₂₆Cl₂N₂O₅ [M + H]⁺Calculated lcms (esi): 493, 495 (3: 2), found 493, 495 (3: 2).

Step d:

will (a) to2R,3S)-2-[4-[(R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]A solution of oxacyclopentane-3-benzoate (0.15 g, 0.30 mmol) in a solution of methylamine in methanol (5 mL) was stirred at room temperature for 16 h. The reaction was concentrated under reduced pressure. The residue was dissolved in aqueous HCl (1)N30 mL) and EA (30 mL). The organic layer was washed with aqueous HCl (1)N2X 30 mL). The combined aqueous layers were concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xselect CSH OBD column 30X 150 mm 5 μm; mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 5% B to 25% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.65 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 260 as an off-white solid (a mixture of (a), (b), and (c))2R,3S)-2-[4-[(R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]Oxetan-3-ol trifluoroacetic acid) (42 mg, 36% of the total of the three steps): C ₁₇H₂₂Cl₂N₂O₄ [M + H]⁺Lcms (esi) calculated value of (a): 389, 391 (3: 2), found 389, 391 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.43 (d, J =4.0 Hz, 1H), 7.08 (s, 1H), 4.75-4.42 (m, 3H), 4.29-3.95 (m, 3H), 3.95-3.87 (m, 1H), 3.18-2.91 (m, 1H), 2.64 (dt, J = 39.0, 12.8 Hz, 1H), 2.50-2.28 (m, 1H), 2.28-2.07 (m, 1H), 2.07-1.87 (m, 2H), 1.57-1.07 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.02.

example 214 Compound 264 (5- [4- [ (()R) -amino (3-chloro-2-fluoro-6-hydroxy-4-methylphenyl) methyl]Piperidine-1-carbonyl]-3-chloro-1H-pyridin-2-one trifluoroethyl fluorideAcid)

Step a:

under nitrogen atmosphere at room temperature with stirringN-[(R) - (3-chloro-2-fluoro-6-hydroxy-4-methylphenyl) (piperidin-4-yl) methyl]-2, 2-Dimethylpropionamide (0.10 g, 0.28 mmol) and Et₃To a solution of N (60 mg, 0.56 mmol) in DMF (2 mL) were added EDC. HCl (80 m, 0.42 mmol) and HOBt (60 mg, 0.42 mmol) and 5-chloro-6-oxo-1H-pyridine-3-carboxylic acid (60 mg, 0.36 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The residue was purified by reverse phase chromatography eluting with 55% aqueous ACN (plus 0.05% TFA) to give a pale yellow foamN-[(R) - (3-chloro-2-fluoro-6-hydroxy-4-methylphenyl) [1- (5-chloro-6-oxo-1H-pyridine-3-carbonyl) piperidin-4-yl]Methyl radical]-2, 2-dimethylpropionamide (0.10 g, 73%): C₂₃H₂₈Cl₂FN₃O₄S [M + H]⁺Calculated lcms (esi): 532, 534 (3: 2), found 532, 534 (3: 2):¹H NMR (400 MHz, CD₃OD) δ 7.85 (t, J = 2.7 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 6.60 (s, 1H), 4.47-4.17 (m, 2H), 3.11-2.86 (m, 2H), 2.40-2.21 (m, 4H), 1.50-1.24 (m, 5H), 1.14 (d, J = 28.3 Hz, 9H)。

step b:

will (a) toS)-N-[(R) - (3-chloro-2-fluoro-6-hydroxy-4-methylphenyl) [1- (5-chloro-6-oxo-1H-pyridine-3-carbonyl) piperidin-4-yl]Methyl radical ]-2-methylpropane-2-sulfinamide (0.10 g, 0.19 mmol) in 1, 4-dioxane (2 mL) and aqueous HCl (6 mL)N1 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: xselect CSH OBD column 30X 150 mm 5 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 5% B to 29% B in 7 minutes; a detector: UV 220 nm; retention time: 6.88 minutes. Collecting the fraction containing the desired product, reducingConcentrating under pressure to obtain 264 (5- [4- [ ((5- [)) in the form of off-white solidR) -amino (3-chloro-2-fluoro-6-hydroxy-4-methylphenyl) methyl]Piperidine-1-carbonyl]-3-chloro-1H-pyridin-2-one trifluoroacetic acid) (56 mg, 55%) (LCMS (ESI) Calculations for C₁₉H₂₀Cl₂FN₃O₃ [M + H]⁺428, 430 (3: 2), found 428, 430 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.85 (d, J = 2.3 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 6.73 (d, J = 1.6 Hz, 1H), 4.47-4.07 (m, 3H), 3.05-2.97 (m, 2H), 2.49 (q, J = 11.1 Hz, 1H), 2.40-2.31 (m, 3H), 2.05 (d, J = 13.0 Hz, 1H), 1.52-1.21 (m, 3H)。¹⁹F NMR (400 MHz, CD₃OD) δ -77.19, -117.77.

EXAMPLE 215 Compound 266 (5- [4- [ (S))R) -amino (3, 4-dichloro-2-fluoro-6-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]-3-chloro-1H-pyridin-2-one trifluoroacetic acid

Step a:

to stirred 5-chloro-6-oxo-1 at room temperatureH-pyridine-3-carboxylic acid (61 mg, 0.35 mmol) and a solution of EDCI (0.12 g, 0.60 mmol) and HOBt (82 mg, 0.60 mmol) in DMF (4 mL) were added portionwise: ( R)-N-[(S) - (3, 4-dichloro-2-fluoro-6-hydroxyphenyl) (piperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide (intermediate 18, example 18) (0.14 g, 0.35 mmol) and Et₃N (0.15 g, 1.51 mmol). After stirring at room temperature for 2 hours, the reaction solution was quenched with water (20 mL) at room temperature and extracted with EA (2X 50 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. Filtering, and concentrating the filtrate under reduced pressure to obtain (A)S)-N-((R) - (1- (5-chloro-6-oxo-1, 6-dihydropyridine-3-carbonyl) piperidin-4-yl) (3, 4-dichloro-2-fluoro-6-hydroxyphenyl) methyl) -2-methylpropane-2-sulfinamide. The crude product was used without further purification in the subsequent step: c₂₂H₂₅Cl₃FN₃O₄S [M + H]⁺Calculated lcms (esi): 552, 554, 556 (3: 3: 1), found 552, 554, 556 (3: 3: 1).

Step b:

stirring at room temperature (S)-N-((R) - (1- (5-chloro-6-oxo-1, 6-dihydropyridine-3-carbonyl) piperidin-4-yl) (3, 4-dichloro-2-fluoro-6-hydroxyphenyl) methyl) -2-methylpropane-2-sulfinamide (crude) to a mixture in THF (4 mL) aqueous HCl (6 mL) was added dropwiseN2 mL). The reaction solution was stirred at room temperature for 2 hours. The reaction solution was stirred at room temperature for 1 hour. The resulting solution was diluted with EA (10 mL). The organic layer was washed with aqueous HCl (1) N3X 10 mL). The combined aqueous layers were washed with EA (3X 10 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xselect CSH OBD column 30 × 150 mm, 5 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 7% B to 30% B in 7 minutes; a detector: UV 220 nm; retention time: 7.80 minutes. Collecting the fractions containing the desired product, concentrating under reduced pressure to obtain compound 266 (5- [4- [ (R))R) -amino (3, 4-dichloro-2-fluoro-6-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]-3-chloro-1H-pyridin-2-one trifluoroacetic acid) (46 mg, 42% of two steps in total): C₁₈H₁₇Cl₃FN₃O₃ [M + H]⁺Calculated lcms (esi): 448, 450, 452 (3: 3: 1), found 448, 450, 452 (3: 3: 1);¹H NMR (400 MHz, CD₃OD) δ 7.84 (d, J = 2.3 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 6.95 (d, J = 1.8 Hz, 1H), 4.43 (d, J = 9.9 Hz, 1H), 4.39-4.03 (m, 2H), 3.14-2.81 (m, 2H), 2.54-2.37 (m, 1H), 2.13-1.93 (m, 1H), 1.53-1.17 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -76.99, -113.23。

example 216 Compound 272 (5- [4- [ (()R) -amino (3-chloro-2-fluoro-6-hydroxy-4-methylphenyl) methyl]Piperidine-1-carbonyl]-1H-pyridin-2-one trifluoroacetic acid

Step a:

to stirred 6-oxo-1 at room temperatureHTo a solution of-pyridine-3-carboxylic acid (44 mg, 0.32 mmol) in DMF (2 mL) were added EDCI (0.10 g, 0.60 mmol) and HOBt (81 mg, 0.60 mmol). Adding (to the mixture at room temperature)S)-N-[(R) - (3-chloro-2-fluoro-6-hydroxy-4-methylphenyl) [1- (6-oxo-1 H-pyridine-3-carbonyl) piperidin-4-yl]Methyl radical]2-methylpropane-2-sulfinamide (0.20 g, 0.40 mmol) and Et₃N (0.12 g, 1.20 mmol). The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was purified by reverse phase chromatography, eluting with 45% aqueous ACN (plus 0.5% TFA) to give (as a colorless oil) ((ii))S)-N-[(R) - (3-chloro-2-fluoro-6-hydroxy-4-methylphenyl) [1- (6-oxo-1H-pyridine-3-carbonyl) piperidin-4-yl]Methyl radical]2-methylpropane-2-sulfinamide (0.12 g, 48%): C₂₃H₂₉ClFN₃O₄S [M + H]⁺Calculated lcms (esi): 498, 500 (3: 1), found 498, 500 (3: 1).

Step b:

stirring at room temperature (S)-N-[(R) - (3-chloro-2-fluoro-6-hydroxy-4-methylphenyl) [1- (6-oxo-1H-pyridine-3-carbonyl) piperidin-4-yl]Methyl radical]-2-methylpropane-2-sulfinamide (0.1 g, 0.20 mmol) in THF (1 mL) aqueous HCl (4) solution was added dropwiseN0.25 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Prep C18 OBD column 19X 150 mm, 5 μm; mobile phase A: water (with 10 mmol/L NH)₄HCO), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 5% B to 30% B in 7 minutes; a detector: UV 254/220 nm; retention time: 5.97 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure to give compound 272 (5- [4- [ (R)) R) -amino (3-chloro-2-fluoro-6-hydroxy-4-methylphenyl) methyl]Piperidine-1-carbonyl]-1H-pyridin-2-one trifluoroacetic acid) (48 mg, 46%): C₁₉H₂₁ClFN₃O₃ [M + H]⁺Calculated lcms (esi): 394, 396 (3: 1), found 394, 396 (3: 1); ¹H NMR (400 MHz, CD₃OD) δ 7.76-7.56 (m, 2H), 6.73 (s, 1H), 6.56 (d, J =9.4 Hz, 1H), 4.54-3.96 (m, 3H), 3.18-2.82 (m, 2H), 2.56-2.43 (m, 1H), 2.35 (s, 3H), 2.12-2.00 (m, 1H), 1.53-1.35 (m, 2H), 1.34-1.18 (m, 1H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.19, -117.75。

example 217 Compound 275 (5- [4- [ (S))R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]-1, 3-diazine-2-one trifluoroacetic acid)

Step a:

to a stirred 3- [ (tert-butoxycarbonyl) amino group at room temperature]-2- [ [ (tert-butoxycarbonyl) amino group]Methyl radical]To a solution of lithium propionate (0.70 g, 2.15 mmol) and HATU (0.81 g, 2.15 mmol) in DMF (6 mL) was added (S)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.60 g, 1.43 mmol) and Et₃N (0.43 g, 4.29 mmol). The reaction was stirred at room temperature for 0.5 h. The residue was purified by reverse phase chromatography, eluting with 60% aqueous ACN (plus 0.05% TFA) and obtained as a pale yellow semi-solidN- (2- [ [ (tert-butoxycarbonyl) amino)]Methyl radical]-3-[4-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidin-1-yl radical]-3-oxopropyl) carbamic acid tert-butyl ester (0.74 g, 72% of the total of the three steps): C₃₃H₅₂Cl₂N₄O₇S [M + H]⁺Calculated lcms (esi): 719, 721 (3: 2), found 719, 721 (3: 2); ¹H NMR (400 MHz, CDCl₃) δ 7.22 (d, J =3.9 Hz, 1H), 6.98 (d, J = 1.9 Hz, 1H), 6.11-5.95 (m, 1H), 5.69-5.49 (m, 2H), 5.49-5.30 (m, 2H), 4.71-4.50 (m, 3H), 4.48-4.21 (m, 1H), 4.05-3.79 (m, 1H), 3.55-3.40 (m, 3H), 3.19-2.89 (m, 4H), 2.59-2.37 (m, 1H), 2.22-1.92 (m, 2H), 1.63-1.36 (m, 19H), 1.33-1.20 (m, 2H), 1.17 (s, 9H)。

Step b:

at room temperature with stirringN- (2- [ [ (tert-butoxycarbonyl) amino)]Methyl radical]-3-[4-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidin-1-yl radical]-3-oxopropyl) carbamic acid tert-butyl ester (0.74 g, 1.03 mmol) in DCM (8 mL) was added TFA (2 mL) dropwise. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated NaHCO at room temperature₃The aqueous solution (6 mL) was neutralized to pH 8. The resulting mixture was extracted with DCM/MeOH (10/1) (3X 100 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with a solution containing 10 mmol/L NH₄HCO₃Eluting with 47% ACN aqueous solution to obtain a pale yellow semisolid (A)S)-N-[(R) - [1- [ 3-amino-2- (aminomethyl) propionyl group]Piperidin-4-yl radical][4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]2-methylpropane-2-sulfinamide (0.20 g, 33%): C₂₃H₃₆Cl₂N₄O₃S [M + H]⁺Calculated lcms (esi): 519, 521 (3: 2), found 519, 521 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.23 (d, J =11.5 Hz, 1H), 6.98 (s, 1H), 6.10-5.96 (m, 1H), 5.47-5.33 (m, 2H), 4.73 (dd, J = 42.4, 13.5 Hz, 1H), 4.62-4.27 (m, 3H), 4.10 (dd, J = 35.9, 13.7 Hz, 1H), 3.94-3.70 (m, 1H), 3.11-2.94 (m, 3H), 2.94-2.78 (m, 2H), 2.59-2.41 (m, 1H), 2.25-1.95 (m, 2H), 1.58-1.19 (m, 3H), 1.16 (d, J = 9.1 Hz, 9H)。

step c:

stirring in the downward direction at 0 ℃: (S)-N-[(R) - [1- [ 3-amino-2- (aminomethyl) propionyl group]Piperidin-4-yl radical][4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ]Methyl radical]To a solution of-2-methylpropane-2-sulfinamide (0.20 g, 0.39 mmol) in DCM (15 mL) was added a solution of CDI (56 mg, 0.35 mmol) in DCM (5 mL). The resulting mixture was stirred at room temperature for 16 hours. Will be provided withThe resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 50% aqueous ACN (plus 0.05% TFA) to give (b) as a colorless oilS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (2-oxo-1, 3-diazine-5-carbonyl) piperidin-4-yl]Methyl radical]2-methylpropane-2-sulfinamide (0.10 g, 48%): C₂₄H₃₄Cl₂N₄O₄S [M + H]⁺Calculated lcms (esi): 545, 547 (3: 2), found 545, 547 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.20 (d, J = 10.2 Hz, 1H), 7.00 (s, 1H), 6.12-5.97 (m, 1H), 5.48-5.25 (m, 2H), 4.76-4.22 (m, 3H), 4.22-3.75 (m, 2H), 3.65-3.49 (m, 2H), 3.49-3.31 (m, 2H), 3.18-2.94 (m, 2H), 2.62-2.35 (m, 1H), 2.35-1.95 (m, 2H), 1.68-1.24 (m, 3H), 1.17 (d, J = 8.5 Hz, 9H)。

step d:

stirring at room temperature (S)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (2-oxo-1, 3-diazine-5-carbonyl) piperidin-4-yl]Methyl radical]-2-methylpropane-2-sulfinamide (0.10 g, 0.18 mmol) and Pd (PPh)₃)₄(2 mg, 0.002 mmol) in THF (1 mL) NaBH was added₄(14 mg, 0.37 mmol). The reaction was quenched with saturated NH at room temperature₄Aqueous Cl (1 mL) was quenched. The resulting mixture was concentrated under reduced pressure to obtain (A) in the form of a yellow oilS)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) [1- (2-oxo-1, 3-diazine-5-carbonyl) piperidin-4-yl]Methyl radical]2-methylpropane-2-sulfinamide (0.10 g, crude), which was used in the next step without further purification: c ₂₁H₃₀Cl₂N₄O₄S [M + H]⁺Lcms (esi) calculated value of (a): 505, 507 (3: 2), found 505, 507 (3: 2).

Step e:

stirring at room temperature (S)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) [1- (2-oxo-1, 3-diazine-5-carbonyl) piperidin-4-yl]Methyl radical]To a mixture of (E) -2-methylpropane-2-sulfinamide (0.10 g, 0.20 mmol) in 1, 4-dioxane (1 mL) was added aqueous HCl (4)N,1 mL). Will be describedThe resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge Prep C18 OBD column, 5 μm, 19 × 150 mm; mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 5% B to 30% B in 7 minutes; a detector: UV 254/220 nm; retention time: 5.68 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure to give compound 275 (5- [4- [ (R))R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]-1, 3-diazinon-2-one trifluoroacetic acid) (50 mg, 53% of two steps in total): C₁₇H₂₂Cl₂N₄O₃ [M + H]⁺Calculated lcms (esi): 401, 403 (3: 2), found 401, 403 (3: 2); ¹H NMR (400 MHz, DMSO-d ₆) δ 7.56 (s, 1H), 7.10 (s, 1H), 4.36 (dd, J =58.0, 13.1 Hz, 1H), 4.17 (t, J = 8.7 Hz, 1H), 3.99 (dd, J = 54.6, 13.8 Hz, 1H), 3.13 (d, J = 8.5 Hz, 4H), 3.07-2.88 (m, 2H), 2.47-2.37 (m, 1H), 2.22-2.07 (m, 1H), 1.90 (t, J = 16.2 Hz, 1H), 1.30-0.85 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.38.

EXAMPLE 218 Compound 284 ((2)R)-1-[4-[(R) -amino [ 5-chloro-2-hydroxy-4- (trifluoromethyl) phenyl ]Methyl radical]Piperidin-1-yl]-2, 3-dihydroxypropan-1-one)

Step a:

stirring at room temperature (4)R) A mixture of-2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid (0.37 g, 2.49 mmol) and HATU (1.18 g, 3.11 mmol) in DMF (10 mL) was added dropwiseN-[(R) - [ 5-chloro-2- (prop-2-en-1-yloxy) -4- (trifluoromethyl) phenyl](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.94 g, 2.08 mmol) and Et₃N (0.42 g, 4.15 mmol). The final reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with water (20 mL). The mixture was washed with EA (3X 5)0 mL) was extracted. The combined organic layers were washed with brine (5X 50 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography using a column containing 20 mmol/L NH₄HCO₃Eluting with 50% ACN aqueous solution to obtain a light yellow oilN-[(R) - [ 5-chloro-2- (prop-2-en-1-yloxy) -4- (trifluoromethyl) phenyl]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]2-methylpropane-2-sulfinamide (0.68 g, 56%): C₂₆H₃₆ClF₃N₂O₅S [M + H]⁺Calculated lcms (esi): 581, 583 (3: 1), found 581, 583 (3: 1).

Step b:

under nitrogen atmosphere at room temperature with stirring N-[(R) - [ 5-chloro-2- (prop-2-en-1-yloxy) -4- (trifluoromethyl) phenyl](1- [ [ (4R) -2, 2-dimethyl-1, 3-di-oxocyclopentan-4-yl)](hydroxy) methyl group]Piperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide (0.68 g, 1.17 mmol) and Pd (PPh)₃)₄(0.13 g, 0.12 mmol) to a mixture in THF (8 mL) NaBH was added portionwise₄(0.88 g, 2.33 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated NH at 0 deg.C₄Aqueous Cl (10 mL) was quenched. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with a solution containing 10 mmol/L NH₄HCO₃Eluting with 45% ACN aqueous solution to obtain the final product in the form of light yellow oilN-[(R) - [ 5-chloro-2-hydroxy-4- (trifluoromethyl) phenyl group]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]2-methylpropane-2-sulfinamide (0.33 g, 47%): C₂₃H₃₂ClF₃N₂O₅S [M + H]⁺Calculated lcms (esi): 541, 543 (3: 1), measured value 541, 543 (3: 1).¹H NMR (400 MHz, CD₃OD) δ 7.46 (d, J = 2.7 Hz, 1H), 7.17 (s, 1H), 4.94-4.83 (m, 1H), 4.65-4.37 (m, 2H), 4.37-4.17 (m, 3H), 3.17-2.95 (m, 2H), 2.73-2.60 (m, 1H), 2.24-2.10 (m, 2H), 1.44-1.32 (m, 8H), 1.16 (d, J = 5.6 Hz, 9H)。

Step c:

at room temperature with stirringN-[(R) - [ 5-chloro-2-hydroxy-4- (trifluoromethyl) phenyl group]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide (0.33 g, 0.61 mmol) in THF (4 mL) aqueous HCl (4) is added dropwiseN2 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was washed with saturated NaHCO ₃The aqueous solution was basified to pH 8. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; a mobile phase A: having a NH concentration of 10 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 15% B to 30% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.5 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 284 ((2) as an off-white solidR)-1-[4-[(R) -amino [ 5-chloro-2-hydroxy-4- (trifluoromethyl) phenyl]Methyl radical]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one) (106.2 mg, 43%). C₁₆H₂₀ClF₃N₂O₄ [M + H]⁺Calculated lcms (esi): 397, 399 (3: 1), found 397, 399 (3: 1):¹H NMR (400 MHz, CD₃OD) δ 7.31 (d, J = 5.1 Hz, 1H), 7.15-7.03 (m, 1H), 4.68-4.46 (m, 2H), 4.12 (dd, J = 40.8, 14.0 Hz, 1H), 3.98 (t, J = 7.8 Hz, 1H), 3.76-3.56 (m, 2H), 3.05 (dt, J = 25.9, 12.8 Hz, 1H), 2.64 (dt, J = 26.8, 12.7 Hz, 1H), 2.14-1.95 (m, 2H), 1.48 (s, 1H), 1.43-1.16 (m, 2H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -63.69.

example 219 the compound 274 (6- [4- [ (R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl ] piperidine-1-carbonyl ] -4-methylmorpholin-3-one isomer 1); compound 278 (6- [4- [ (R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl ] piperidine-1-carbonyl ] -4-methylmorpholin-3-one isomer 2)

Step a:

separation of 6- [4- [ ((s)) by preparative chiral HPLC under the following conditionsR) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]-4-methylmorpholin-3-one trifluoroacetic acid (66.5 mg 0.13 mmol) column: CHIRALPAK IF, 2X 25 cm, 5 μm; mobile phase A: hexane (plus 0.2% IPA), mobile phase B: EtOH; flow rate: 19 mL/min; gradient: from 40% B to 40% B in 22 minutes; a detector: UV 220/254 nm; retention time: RT (reverse transcription) ₁12.67 minutes; RT (reverse transcription)₂17.32 minutes; injection volume 0.6 mL.

The faster eluting enantiomer was obtained as compound 278 (6- [4- [ (R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) in the form of an off-white solid at 12.67 minutes]Piperidine-1-carbonyl]4-methylmorpholin-3-one isomer 2) (18.1 mg, 11%): C₁₈H₂₃Cl₂N₃O₄ [M + H]⁺Lcms (esi) calculated value: 416, 418 (3: 2), found 416, 418 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.23 (s, 1H), 6.88 (s, 1H), 4.81-4.66 (m, 1H), 4.53 (dd, J = 41.3, 13.4 Hz, 1H), 4.30-4.16 (m, 2H), 4.14-3.97 (m, 1H), 3.91 (dd, J = 18.3, 7.7 Hz, 1H), 3.74 (dd, J = 12.1, 8.6 Hz, 1H), 3.45-3.35 (m, 1H), 3.19-2.94 (m, 4H), 2.72-2.53 (m, 1H), 2.16-1.92 (m, 2H), 1.59-1.43 (m, 1H), 1.38-1.04 (m, 2H)。

the slower eluting enantiomer was obtained as compound 274 (6- [4- [ (R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) in the form of an off-white solid at 17.32 min]Piperidine-1-carbonyl]-4-methylmorpholin-3-one isomer 1) (17.3 mg, 11%): C₁₈H₂₃Cl₂N₃O₄ [M + H]⁺Lcms (esi) calculated value: 416, 418 (3: 2), found 416, 418 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.23 (d, J = 7.5 Hz, 1H), 6.88 (d, J = 3.0 Hz, 1H), 4.75 (td, J = 8.2, 3.8 Hz, 1H), 4.52 (dd, J = 35.4, 13.3 Hz, 1H), 4.31-4.06 (m, 2H), 4.12-3.98 (m, 1H), 3.91 (dd, J = 7.6, 2.4 Hz, 1H), 3.80-3.68 (m, 1H), 3.46-3.35 (m, 1H), 3.12-2.98 (m, 4H), 2.75-2.51 (m, 1H), 2.16-1.95 (m, 2H), 1.51 (t, J = 15.2 Hz, 1H), 1.40-1.04 (m, 2H)。

EXAMPLE 220 Compound 276 (6- [4- [ (R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl ] piperidine-1-carbonyl ] morpholin-3-one isomer 2)

Step a:

separation of 6- [4- [ (ii) by chiral preparative HPLC under the following conditionsR) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]Morpholin-3-one (0.12 g, 0.23 mmol) column: CHIRALPAK IG, 2X 25 cm, 5 μm; mobile phase A: MTBE (plus 0.2% IPA), mobile phase B: EtOH; flow rate: 20 mL/min; gradient: from 10% B to 10% B in 21 minutes; a detector: UV 220/254 nm; retention time: RT (reverse transcription) ₁12.96 minutes; RT (reverse transcription)₂18.67 minutes; injection volume 0.3 mL; the number of tests was 17.

The faster eluting enantiomer was obtained as (6) as an off-white solid at 12.96 minS)-6-[4-[(R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]Morpholine-3-one (37 mg, 41%): C₁₇H₂₁Cl₂N₃O₄ [M + H]⁺Calculated lcms (esi): 402, 404 (3: 2), measured 402, 404 (3: 2); ¹H NMR (400 MHz, CD₃OD) δ 7.23 (d, J = 5.6 Hz, 1H), 6.88 (s, 1H), 4.70-4.43 (m, 2H), 4.34-3.98 (m, 2H), 3.98-3.76 (m, 1H), 3.69-3.57 (m, 1H), 3.45-3.34 (m, 1H), 3.21-2.89 (m, 1H), 2.78-2.50 (m, 1H), 2.28-1.65 (m, 3H), 1.60-1.40 (m, 1H), 1.40-1.02 (m, 2H)。

the slower eluting enantiomer was obtained as compound 276 (6- [4- [ (R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) in the form of an off-white solid]Piperidine-1-carbonyl]Morpholine-3-one isomer 2) (41 mg, 44%): C₁₇H₂₁Cl₂N₃O₄ [M + H]⁺Calculated lcms (esi): 402, 404 (3: 2), measured 402, 404 (3: 2); ¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 6.88 (s, 1H), 4.72-4.43 (m, 2H), 4.24 (qd, J = 16.6, 3.7 Hz, 2H), 4.07 (dd, J = 40.0, 13.5 Hz, 1H), 3.91 (dd, J = 16.3, 7.7 Hz, 1H), 3.65 (dd, J = 12.8, 9.0 Hz, 1H), 3.45-3.35 (m, 1H), 3.19-2.92 (m, 1H), 2.72-2.56 (m, 1H), 2.12-1.94 (m, 2H), 1.56-1.40 (m, 1H), 1.40-1.11 (m, 2H)。

example 221 Compound 318 ((2)R)-1-[4-[(R) -amino [ 5-chloro-4- (cyclopent-1-en-1-yl) -2-hydroxyphenyl]Methyl radical]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid)

Step a:

stirring at room temperature (S)-N-[(R) - (4-bromo-5-chloro-2-methoxyphenyl) ([1- [ (4)R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]To a mixture of (2-methylpropane-2-sulfinamide) (intermediate 23, example 23) (0.10 g, 0.18 mmol) in DCM (2 mL) was added BBr₃(0.27 g, 1.06 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (3 mL) at 0 ℃. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 30% aqueous ACN (plus 0.05% TFA) to give (2) as a pale yellow oil R)-1-[4-[(R) -amino (4-bromo-5-chloro-2-hydroxyphenyl) methyl]Piperidin-1-yl]-2, 3-dihydroxypropan-1-one (60 mg, 67%): C₁₅H₂₀BrClN₂O₄ [M + H]⁺Calculated lcms (esi): 407, 409, 411 (2: 3: 1), found 407, 409, 411 (2: 3: 1);¹H NMR (400 MHz, CD₃OD) δ 7.43 (s, 1H), 7.25 (s, 1H), 4.71-4.43 (m, 1H), 4.30-4.05 (m, 2H), 3.76-3.58 (m, 2H), 3.19-2.95 (m, 1H), 2.67 (dt, J = 42.6, 12.9 Hz, 1H), 2.48-2.31 (m, 1H), 2.08-1.97 (m, 2H), 1.48-1.07 (m, 3H)。

step b:

to (2)R)-1-[4-[(R) -amino (4-bromo-5-chloro-2-hydroxyphenyl) methyl]Piperidin-1-yl radical]-2,To a solution of 3-dihydroxypropan-1-one (30 mg, 0.07 mmol) and 2- (cyclopent-1-en-1-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (29 mg, 0.15 mmol) in 1, 4-dioxane (2 mL) and water (0.5 mL) was added Na₂CO₃(23 mg, 0.22 mmol) and Pd (dppf) Cl₂·CH₂Cl₂(12 mg, 0.02 mmol). The reaction mixture was degassed three times with nitrogen. After stirring at 80 ℃ for 2 hours under nitrogen, the resulting mixture was cooled to room temperature and diluted with EA (15 mL). The resulting solution was taken up in aqueous HCl (1)N3X 10 mL). The combined aqueous layers were concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xselect CSH OBD column 30X 150 mm 5 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 8% B to 35% B in 7 minutes; a detector: UV 220/254 nm; retention time: 6.50 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure to give compound 318 ((2) as an off-white solid R)-1-[4-[(R) -amino [ 5-chloro-4- (cyclopent-1-en-1-yl) -2-hydroxyphenyl]Methyl radical]Piperidin-1-yl]-2, 3-dihydroxypropan-1-one trifluoroacetic acid) (12 mg, 33%): C₂₀H₂₇ClN₂O₄ [M + H]⁺Calculated lcms (esi): 395, 397 (3: 1), found 395, 397 (3: 1);¹H NMR (400 MHz, CD₃OD) δ 7.28 (s, 1H), 6.88 (s, 1H), 6.14 (q, J = 2.3 Hz, 1H), 4.71-4.46 (m, 2H), 4.28-4.03 (m, 2H), 3.83-3.56 (m, 2H), 3.17-2.95 (m, 1H), 2.78-2.61 (m, 3H), 2.59-2.51 (m, 2H), 2.48-2.30 (m, 1H), 2.08-1.88 (m, 3H), 1.50-1.11 (m, 3H)。

EXAMPLE 222 Compound 282 ((2)R)-1-(4-((R) -amino (5-chloro-2-hydroxy-4-isopropylphenyl) methyl) piperidin-1-yl) -2, 3-dihydroxypropan-1-one

Step a:

stirring under nitrogen atmosphere at room temperatureS)-N-[(R) - (4-bromo-5-chloro-2-methoxyphenyl) ([1- [ (4)R) -2, 2-bisMethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide (intermediate 23, example 23) (0.50 g, 0.88 mmol) and 4,4,5, 5-tetramethyl-2- (prop-1-en-2-yl) -1,3, 2-dioxaborolan (0.22 g, 1.32 mmol) in 1, 4-dioxane (5 mL) and H₂To a solution in O (1.25 mL) was added Na₂CO₃ (0.28 g, 2.65 mmol) and Pd (dppf) Cl₂·CH₂Cl₂ (72 mg, 0.08 mmol). The resulting mixture was degassed three times with nitrogen and stirred under nitrogen at 80 ℃ for 2 hours. The resulting mixture was diluted with EA (20 mL) and water (30 mL). The aqueous layer was extracted with EA (3X 40 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 50% aqueous ACN (plus 0.05% TFA) and afforded (b) as a yellow solid S)-N-[(R) - [ 5-chloro-2-methoxy-4- (prop-1-en-2-yl) phenyl]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]2-methylpropane-2-sulfinamide (0.37 g, 79%): C₂₆H₃₉ClN₂O₅S [M + H]⁺Calculated lcms (esi): 527, 529 (3: 1), found 527, 529 (3: 1);¹H NMR (400 MHz, CDCl₃) δ 7.11 (d, J =20.5H, z, 1H), 6.73 (s, 1H), 5.30-5.22 (m, 1H), 5.02 (d,J = 5.1 Hz, 1H), 4.74-4.61 (m, 2H), 4.61-4.43 (m, 1H), 4.43-4.28 (m, 1H), 4.28-4.05 (m, 2H), 3.84 (s, 3H), 3.12-2.85 (m, 1H), 2.55 (t, J = 12.7 Hz, 1H), 2.13 (s, 3H), 2.05-1.91 (m, 2H), 1.68-1.48 (m, 3H), 1.45-1.38 (m, 6H), 1.18 (d, J = 12.9 Hz, 9H)。

step b:

stirring at room temperature under air atmosphere (S)-N-[(R) - [ 5-chloro-2-methoxy-4- (prop-1-en-2-yl) phenyl]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide (0.10 g, 0.19 mmol) in MeOH (2 mL) to which PtO was added₂(30 mg, 0.13 mmol). The resulting mixture was degassed three times with hydrogen and under hydrogen atmosphere (1.5 atm)The mixture was stirred at room temperature for 1 hour. The resulting mixture was filtered. The filter cake was washed with MeOH (3X 30 mL). The filtrate was concentrated under reduced pressure to give (A) as a brown oilS)-N-[(R) - (5-chloro-4-isopropyl-2-methoxyphenyl) ([1- [ (4)R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]2-methylpropane-2-sulfinamide (0.10 g, 99%): C₂₆H₄₁ClN₂O₅S [M + H]⁺Calculated lcms (esi): 529, 531 (3: 1), found 529, 531 (3: 1);¹H NMR (400 MHz, CD₃OD)δ 7.26 (d, J = 2.0 Hz, 1H), 6.93 (s, 1H), 4.58-4.35 (m, 2H), 4.30-3.98 (m, 3H), 3.87 (s, 3H), 3.44-3.37 (m, 1H), 3.18-2.88 (m, 1H), 2.63 (dt, J =23.0, 12.6 Hz, 1H), 2.26-1.97 (m, 3H), 1.48-1.30 (m, 7H), 1.30-1.21 (m, 8H), 1.14 (d, J = 7.7 Hz, 9H)。

step c:

Stirring at room temperature (S)-N-[(R) - (5-chloro-4-isopropyl-2-methoxyphenyl) [1- (2, 2-dimethyl-1, 3-dioxolane-4-carbonyl) piperidin-4-yl group]Methyl radical]To a solution of (E) -2-methylpropane-2-sulfinamide (0.10 g, 0.19 mmol) in DCM (2 mL) was added BBr₃(0.47 g, 1.89 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction was washed with MeOH (2 mL) at 0^oAnd C, quenching. The mixture was washed with saturated NaHCO₃The aqueous solution (5 mL) was neutralized to pH 7. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD column 30X 150 mm, 5 μm; mobile phase A: having a NH concentration of 10 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 25% B to 45% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.50 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure to give compound 282 ((2) as an off-white solidR)-1-[4-[(R) -amino (5-chloro-2-hydroxy-4-isopropylphenyl) methyl]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one) (16 mg, 22% of two steps in total): C₁₈H₂₇ClN₂O₄ [M + H]⁺Calculated lcms (esi): 371, 373 (3: 1), found 371, 373 (3): 1)； ¹H NMR (400 MHz, CD₃OD) δ 7.10 (s, 1H), 6.76 (s, 1H), 4.65-4.44 (m, 2H), 4.11 (dd, J = 46.7, 13.7 Hz, 1H), 3.85 (d, J = 7.2 Hz, 1H), 3.78-3.55 (m, 2H), 3.30-3.26 (m, 1H), 3.11-2.93 (m, 1H), 2.75-2.49 (m, 1H), 2.07-1.93 (m, 2H), 1.58-1.38 (m, 1H), 1.38-1.07 (m, 8H)。

Example 223 Compound 283 ((2)R)-1-[4-[(R) -amino (5-fluoro-2-hydroxy-4-methylphenyl) methyl ]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one)

Step a:

stirring under nitrogen atmosphere at room temperatureS)-N-[(R)-[1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical][ 5-fluoro-4-methyl-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]-2-methylpropane-2-sulfinamide (30 mg, 0.06 mmol) and Pd (PPh)₃)₄(7 mg, 0.006 mmol) in THF (2 mL) NaBH was added₄(5 mg, 0.12 mmol). The resulting mixture was stirred at room temperature for 30 minutes under nitrogen atmosphere. The reaction was quenched with saturated NH at room temperature₄Aqueous Cl (2 mL) was quenched. Concentrated under reduced pressure to give (S)-N-[(R)-[1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical](5-fluoro-2-hydroxy-4-methylphenyl) methyl]2-methylpropane-2-sulfinamide (20 mg, crude): C₂₃H₃₅FN₂O₅S [M + H]⁺Calculated lcms (esi): 471, found value 471.

Step b:

under the atmosphere of air, at room temperatureS)-N-[(R)-[1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical](5-fluoro-2-hydroxy-4-methylphenyl) methyl]2-methylpropane-2-sulfinamide (20 mg, 0.042 mmol) and aqueous HCl (6)N0.50 mL) in 1, 4-dioxane (1 mL) was stirred for 1 hour. The resulting mixture was concentrated under reduced pressure. Removing residuesThe residue was purified by preparative HPLC under the following conditions: column: xbridge Prep C18 OBD column, 5 μm, 19X 150 mm; mobile phase A: having a NH concentration of 10 mmol/L ₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 5% B to 32% B in 7 minutes; a detector: UV 220 nm; retention time: 7.38 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 283 ((2) as an off-white solidR)-1-[4-[(R) -amino (5-fluoro-2-hydroxy-4-methylphenyl) methyl]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one) (4 mg, 29%): C₁₆H₂₃FN₂O₄ [M + H]⁺Calculated lcms (esi): 327, measured value 327;¹H NMR (400 MHz, CD₃OD) δ 6.82 (d, J = 10.2 Hz, 1H), 6.63 (d, J = 6.7 Hz, 1H), 4.61 (d, J = 13.6 Hz, 1H), 4.53-4.46 (m, 1H), 4.11 (dd, J = 48.1, 13.8 Hz, 1H), 3.88 (d, J = 8.3 Hz, 1H), 3.70-3.57 (m, 2H), 3.09-2.99 (m, 1H), 2.70-2.60 (m, 1H), 2.19 (s, 3H), 2.07-1.94 (m, 2H), 1.51-1.42 (m, 1H), 1.40-1.15 (m, 2H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -131.97.

example 224. Compound 285 (2)R)-1-[4-[(R) -amino (5-chloro-4-fluoro-2-hydroxyphenyl) methyl group]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid

Step a:

to a stirred solution of 1-bromo-5-chloro-4-fluoro-2- (prop-2-en-1-yloxy) benzene (intermediate 21, example 21) (0.60 g, 2.25 mmol) in THF (3 mL) at 0 deg.C under a nitrogen atmosphere was added dropwisei-PrMgCl (2.25 mL, 2.25 mmol, 2M in THF). The reaction mixture was stirred at 0 ℃ for 30 minutes. A solution of tert-butyl 4-formylpiperidine-1-carboxylate (0.40 g, 1.88 mmol) in THF (4 mL) was then added dropwise to the above solution at 0 deg.C. The resulting solution was stirred at 0 ℃ for an additional 1 hour. Reacting with saturated NH₄Aqueous Cl (1 mL) was quenched. The resulting mixture was diluted with water (30 mL) and then water was added The layers were extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography, eluting with PE/EA (2/1), and obtaining 4- [ [ 5-chloro-4-fluoro-2- (prop-2-en-1-yloxy) phenyl ] in the form of pale yellow oil](hydroxy) methyl group]Piperidine-1-carboxylic acid tert-butyl ester (0.60 g, 80%) C₂₀H₂₇ClFNO₄ [M + H]⁺Calculated lcms (esi): 400, 402 (3: 1), found 400, 402 (3: 1);¹H NMR (400 MHz, CDCl₃) δ 7.36 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 10.8 Hz, 1H), 6.10-5.96 (m, 1H), 5.39 (dd, J = 24.6, 13.8 Hz, 2H), 4.71 (d, J = 7.1 Hz, 1H), 4.55 (d, J = 4.6 Hz, 2H), 4.24-4.06 (m, 3H), 2.77-2.50 (m, 2H), 1.95-1.68 (m, 2H), 1.47 (d, J = 2.6 Hz, 9H), 1.45-1.20 (m, 3H)。

step b:

to a stirred 4- [ [ 5-chloro-4-fluoro-2- (prop-2-en-1-yloxy) phenyl group at room temperature](hydroxy) methyl group]To a solution of tert-butyl piperidine-1-carboxylate (0.60 g, 1.50 mmol) in DCM (4 mL) was added dess-martin reagent (0.95 g, 2.25 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was saturated with Na₂SO₃Aqueous solution (5 mL) was quenched. The resulting mixture was diluted with EA (30 mL) and water (30 mL), and the aqueous layer was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with PE/EA (8/1) to give 4- [ 5-chloro-4-fluoro-2- (prop-2-en-1-yloxy) benzoyl group as a pale yellow oil ]Piperidine-1-carboxylic acid tert-butyl ester (0.60 g, 98%): C₂₀H₂₅ClFNO₄ [M + Na]⁺Lcms (esi) calculated value of (a): 420, 422 (3: 1), found 420, 422 (3: 1);¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, J = 8.6 Hz, 1H), 6.79 (d, J = 10.6 Hz, 1H), 6.15-5.98 (m, 1H), 5.58-5.33 (m, 2H), 4.62 (d, J = 5.7 Hz, 2H), 4.29-4.06 (m, 3H), 3.47-3.33 (m, 1H), 2.93-2.62 (m, 3H), 1.96-1.68 (m, 2H), 1.48 (s, 9H)。

step c:

to a stirred 4- [ 5-chloro-4-fluoro-2- (prop-2-en-1-yloxy) benzoyl group at room temperature]Piperidine-1-carboxylic acid tert-butyl ester (0.60 g, 1.51 mmol) and (C) (B)S) (iii) -2-methylpropane-2-sulfinamide (0.55 g, 4.52 mmol) in THF (4 mL) Ti (OEt)₄(3.44 g, 15.08 mmol). The reaction was warmed to 70 ℃ and stirred under nitrogen for 16 hours. The reaction solution was saturated with Na₂CO₃Aqueous solution (30 mL) was quenched. The resulting mixture was filtered through celite (celite). The filtrate was diluted with water (30 mL) and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography, eluting with PE/EA (2/1), and obtaining 4- [ [ 5-chloro-4-fluoro-2- (prop-2-en-1-yloxy) phenyl ] in the form of pale yellow oil]([[(S) -2-methylpropan-2-sulfinyl]Imino radical]) Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester (0.53 g, 70%): C₂₄H₃₄ClFN₂O₄S [M + H]⁺Calculated lcms (esi): 501, 503 (3: 1), found 501, 503 (3: 1);¹H NMR (400 MHz, CDCl₃) δ 7.12 (s, 1H), 6.72 (d, 2.9 Hz, 1H), 6.09-5.91 (m, 1H), 5.37 (dd, J = 33.6, 14.0 Hz, 2H), 4.58 (s, 2H), 4.23-4.07 (m, 1H), 2.90-2.55 (m, 4H), 1.95-1.83 (m, 1H), 1.83-1.64 (m, 1H), 1.65-1.54 (m, 2H), 1.48 (s, 9H), 1.23 (s, 9H)

step d:

4- [ (ii) stirred at-70 ℃ under nitrogen atmosphere 1E) - [ 5-chloro-4-fluoro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Imino radical]) Methyl radical]To a solution of piperidine-1-carboxylic acid tert-butyl ester (0.53 g, 1.06 mmol) in THF (5 mL) was added DIBAL-H (2.08 mL, 2.08 mmol, 1M in toluene) dropwise. The resulting solution was stirred at-70 ℃ for 1 hour under nitrogen. Reacting with saturated NH₄Aqueous Cl (1 mL) was quenched. The resulting mixture was diluted with EA (30 mL) and water (30 mL), and the aqueous layer was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying.After filtration, the filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography, eluting with PE/EA (2/1), to obtain 4- [ (R) ((R) ()) as an off-white solidR) - [ 5-chloro-4-fluoro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester (0.43 g, 81%): C₂₄H₃₆ClFN₂O₄S [M + H]⁺Calculated lcms (esi): 503, 505 (3: 1), measured 503, 505 (3: 1);¹H NMR (400 MHz, CDCl₃) δ 7.18 (d, J = 8.3 Hz, 1H), 6.71 (d, J =10.7 Hz, 1H), 6.11-5.93 (m, 1H), 5.48-5.28 (m, 2H), 4.64-4.39 (m, 2H), 4.31-4.04 (m, 1H), 4.23-4.04 (m, 1H), 3.83-3.61 (m, 1H), 2.74-2.52 (m, 2H), 2.03-1.78 (m, 2H), 1.62-1.60 (m, 3H), 1.46 (s, 9H), 1.17 (s, 9H)。

step e:

4- [ (ii) to stirring at room temperatureR) - [ 5-chloro-4-fluoro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]To a solution of tert-butyl piperidine-1-carboxylate (0.20 g, 0.40 mmol) in DCM (5 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 0.5 h. The reaction was saturated with Na ₂CO₃The aqueous solution was neutralized to pH 8. The resulting mixture was diluted with water (20 mL) and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 40 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to obtain (A) as a pale yellow oilS)-N-[(R) - [ 5-chloro-4-fluoro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.16 g, crude), which was used in the next step without further purification: c₁₉H₂₈ClFN₂O₂S [M + H]⁺Calculated lcms (esi): 403, 405 (3: 1), found 403, 405 (3: 1);¹H NMR (400 MHz, CDCl₃) δ 7.20 (d, J = 8.3 Hz, 1H), 6.73 (d, J = 10.6 Hz, 1H), 6.09-5.89 (m, 1H), 5.48-5.31 (m, 2H), 4.68-4.49 (m, 2H), 4.49-4.32 (m, 1H), 4.32-4.23 (m, 1H), 3.42 (dd, J = 33.0, 12.6 Hz, 1H), 2.91-2.71 (m, 2H), 2.38-2.12 (m, 1H), 2.12-1.94 (m, 1H), 1.78-1.51 (m, 3H), 1.14 (s, 9H)。

step f:

stirring at room temperature (4R) (2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid (87 mg, 0.60 mmol) and HATU (0.23 g, 0.60 mmol) in DMF (2 mL) was addedS)-N-[(R) - [ 5-chloro-4-fluoro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.16 g, 0.40 mmol) and Et₃N (80 mg, 0.79 mmol). The reaction was stirred at room temperature for 0.5 h. The resulting solution was quenched with water (50 mL) and extracted with EA (3X 40 mL). The combined organic layers were washed with brine (2X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 58% aqueous ACN (plus 0.05% TFA) to give (b) as a colorless oil S)-N-[(R) - [ 5-chloro-4-fluoro-2- (prop-2-en-1-yloxy) phenyl]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]2-methylpropane-2-sulfinamide (0.18 g, 85%): C₂₅H₃₆ClFN₂O₅S [M + H]⁺Calculated lcms (esi): 531, 533 (3: 1), found 531, 533 (3: 1).

Step g:

stirring at room temperature (S)-N-[(R) - [ 5-chloro-4-fluoro-2- (prop-2-en-1-yloxy) phenyl]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide (0.18 g, 0.34 mmol) and Pd (PPh)₃)₄(4 mg, 0.003 mmol) in THF (3 mL) NaBH was added₄(26 mg, 0.69 mmol). The reaction was stirred at room temperature for 1 hour. The reaction solution was quenched with water (0.5 mL) and concentrated under reduced pressure to give (A) as an off-white solidS)-N-[(R) - (5-chloro-4-fluoro-2-hydroxyphenyl) ([1- [ (2)R) -2, 3-dihydroxypropanoyl group]Piperidin-4-yl radical]) Methyl radical]2-methylpropane-2-sulfinamide (0.15 g, crude), which is used directly in the subsequent step without further purification C₁₉H₂₈ClFN₂O₅S [M + H]⁺Calculated lcms (esi): 451, 453 (3: 1) Measured value 451, 453 (3: 1);

step h:

stirring at room temperature (S)-N-[(R) - (5-chloro-4-fluoro-2-hydroxyphenyl) ([1- [ (2)R) -2, 3-dihydroxypropanoyl group]Piperidin-4-yl radical]) Methyl radical ](iii) solution of (E) -2-methylpropane-2-sulfinamide (0.13 g, 0.29 mmol) in 1, 4-dioxane (2 mL) was added aqueous HCl (4)N2 mL). The resulting solution was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xselect CSH OBD column 30X 150 mm 5 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 5% B to 18% B in 7 minutes; a detector: UV 254/220 nm; retention time: 5.95 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure to give compound 285 ((2) as an off-white solidR)-1-[4-[(R) -amino (5-chloro-4-fluoro-2-hydroxyphenyl) methyl group]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid) (30 mg, 25% of two steps in total) C₁₅H₂₀ClFN₂O₄ [M + H]⁺Calculated lcms (esi): 347, 349 (3: 1), found 347, 349 (3: 1);¹H NMR (400 MHz, CD₃OD) δ 7.39 (d, J = 8.1 Hz, 1H), 6.81 (d, J =10.5 hours z, 1H), 4.72-4.45 (m, 2H), 4.36-3.97 (m, 2H), 3.77-3.57 (m, 2H), 3.20-2.95 (m, 1H), 2.81-2.56 (m, 1H), 2.46-2.29 (m, 1H), 2.14-1.94 (m, 1H), 1.51-1.09 (m, 3H);¹⁹F NMR (376 MHz, CD₃OD) δ -77.20, -114.76.

example 225 Compound 286 (4- [ (()R) -amino ([1- [ (2)R) -2, 3-dihydroxypropanoyl group]Piperidin-4-yl radical]) Methyl radical]-2-chloro-5-hydroxybenzonitrile trifluoroacetic acid)

A, step a:

under nitrogen atmosphere, stirring at room temperatureS)-N-[(R) - (4-bromo-5-chloro-2-methoxyphenyl) ([1- [ (4)R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidine-4-Base (C)]) Methyl radical]-2-methylpropane-2-sulfinamide (intermediate 23, example 23) (90 mg, 0.16 mmol) and Pd (PPh)₃)₄(18 mg, 0.02 mmol) in NMP (2 mL) with Zn (CN)₂(37 mg, 0.32 mmol). The reaction mixture was irradiated with microwave radiation at 150 ℃ for 2 hours. The reaction was quenched with saturated NaHCO at room temperature₃The aqueous solution was quenched. The resulting mixture was diluted with water (20 mL) and extracted with EA (3X 20 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 50% aqueous ACN (plus 0.05% TFA) to give (a) as an off-white solidS)-N-[(R) - (5-chloro-4-cyano-2-methoxyphenyl) ([1- [ (4)R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]2-methylpropane-2-sulfinamide (20 mg, 17%): C₂₄H₃₄ClN₃O₅S [M + H]⁺Calculated lcms (esi): 512, 514 (3: 1), found 512, 514 (3: 1);¹H NMR (400 MHz, CDCl₃) δ 7.27-7.20 (m, 1H), 7.13 (s, 1H), 4.71-4.60 (m, 2H), 4.59-4.36 (m, 1H), 4.29-4.07 (m, 2H), 3.92-3.77 (m, 4H), 2.97 (dt, J =63.9, 13.0 Hz, 1H), 2.53 (t, J = 12.8 Hz, 1H), 2.20-2.09 (m, 1H), 2.03-1.91 (m, 1H), 1.53-1.24 (m, 9H), 1.18 (d, J = 10.6 Hz, 9H)。

step b:

stirring at room temperature (S)-N-[(R) - (5-chloro-4-cyano-2-methoxyphenyl) ([1- [ (4) R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl]) Methyl radical]To a solution of (E) -2-methylpropane-2-sulfinamide (20 mg, 0.04 mmol) in DCM (2 mL) was added BBr₃(59 mg, 0.23 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (1 mL) at 0 ℃. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xselect CSH OBD column 30 × 150 mm 5 μm, n; mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 5% B to 23% B in 7 minutes; a detector: UV 220/254 nm; retention time: 6.03And (3) minutes. The fractions containing the desired product were collected, concentrated under reduced pressure to give compound 286 (4- [ (4-)) as an orange solidR) -amino ([1- [ (2)R) -2, 3-dihydroxypropanoyl group]Piperidin-4-yl radical]) Methyl radical]-2-chloro-5-hydroxybenzonitrile trifluoroacetic acid) (4 mg, 22%): C₁₆H₂₀ClN₃O₄ [M + H]⁺Calculated lcms (esi): 354, 356 (3: 1), found 354, 356 (3: 1);¹H NMR (400 MHz, CD₃OD) δ 7.55 (s, 1H), 7.27 (s, 1H), 4.71-4.44 (m, 2H), 4.30-4.05 (m, 2H), 3.76-3.56 (m, 2H), 3.20-2.95 (m, 1H), 2.66 (dt, J = 44.9, 12.9 Hz, 1H), 2.48-2.31 (m, 1H), 2.09-1.95 (m, 1H), 1.50-1.13 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -76.93.

example 226 compound 287 ((R) -1- (4- ((S) -amino (3, 4-dichloro-2-fluoro-6-hydroxyphenyl) methyl) piperidin-1-yl) -2, 3-dihydroxypropan-1-one); compound 291 ((R) -1- (4- ((R) -amino (3, 4-dichloro-2-fluoro-6-hydroxyphenyl) methyl) piperidin-1-yl) -2, 3-dihydroxypropan-1-one)

A, step a:

separation by chiral preparative HPLC under the following conditions (2)R) -1- [4- [ amino (3, 4-dichloro-2-fluoro-6-hydroxyphenyl) methyl]Piperidin-1-yl]-2, 3-dihydroxypropan-1-one (106.00 mg): column: CHIRALPAK IG, 20X 250 mm, 5 μm; a mobile phase A: hexane (plus 0.2% IPA), mobile phase B: EtOH; flow rate: 20 mL/min; gradient: from 30% B to 30% B in 23 minutes; a detector: UV 220/254 nm; retention time: RT (reverse transcription)₁13.338 minutes; RT (reverse transcription)₂18.463 minutes; injection volume 0.4 ml.

The faster eluting enantiomer was obtained as compound 291 (,(s) as an off-white solid at 7.47 minutesR)-1-(4-((R) -amino (3, 4-dichloro-2-fluoro-6-hydroxyphenyl) methyl) piperidin-1-yl) -2, 3-dihydroxypropan-1-one) (31 mg, 29%): C₁₅H₁₉Cl₂FN₂O₄ [M + H]⁺Calculated lcms (esi): 381, 383 (32), found 381, 383 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 6.66 (s, 1H), 4.68-4.44 (m, 2H), 4.27-4.04 (m, 2H), 3.81-3.50 (m, 2H), 3.21-2.96 (m, 1H), 2.77-2.59 (m, 1H), 2.31-2.16 (m, 1H), 2.05 (d, J = 9.6 Hz, 1H), 1.56 (d, J = 13.3 Hz, 1H), 1.46-1.15 (m, 2H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -116.15.

the slower eluting enantiomer was obtained as compound 287 ((R) -1- (4- ((S) -amino (3, 4-dichloro-2-fluoro-6-hydroxyphenyl) methyl) piperidin-1-yl) -2, 3-dihydroxypropan-1-one) (28 mg, 26%) as an off-white solid at 10.05 min: (C)₁₅H₁₉Cl₂FN₂O₄ [M + H]⁺Calculated lcms (esi): 381, 383 (3: 2), found 381, 383 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 6.66 (s, 1H), 4.68-4.44 (m, 2H), 4.27-4.04 (m, 2H), 3.81-3.50 (m, 2H), 3.21-2.96 (m, 1H), 2.77-2.59 (m, 1H), 2.31-2.16 (m, 1H), 2.05 (d, J = 9.6 Hz, 1H), 1.56 (d, J = 13.3 Hz, 1H), 1.46-1.15 (m, 2H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -116.15.

example 227 Compound 288 (, (2R)-1-[4-[(R) -amino (5-chloro-4-cyclobutyl-2-hydroxyphenyl) methyl group ]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid)

Step a:

to a stirred solution of 1-bromo-5-chloro-4-cyclobutyl-2-methoxybenzene (0.24 g, 0.87 mmol) in THF (4 mL) was added dropwise under a nitrogen atmosphere at-78 deg.Cn-BuLi (0.35 mL, 0.88 mmol, 2.5M in hexane). The reaction solution was stirred at-78 ℃ for 30 minutes. Then will (S)-N-([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]A solution of methylene) -2-methylpropane-2-sulfinamide (0.15 g, 0.44 mmol) in THF (3 mL) was added to the solution. The resulting solution was stirred at-78 ℃ for an additional 2 hours. Reacting with saturated NH₄Aqueous Cl (1 mL) was quenched and diluted with water (30 mL). The aqueous layer was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 43% aqueous ACN (plus 0.05% TFA) to give (b) as a colorless oilS)-N-[(R) - (5-chloro-4-cyclobutyl-2-methoxyphenyl) (piperidin-4-yl) methyl]-2-methylpropane-2-sulfinylamide trifluoroacetic acid (0.12 g, 64%): C₂₁H₃₃ClN₂O₂S [M + H]⁺Calculated lcms (esi): 413, 415 (3: 1), measured 413, 415 (3: 1);¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 6.98 (s, 1H), 4.48 (d, J = 9.0 Hz, 1H), 3.90 (s, 3H), 3.85-3.72 (m, 1H), 3.47 (d, J = 13.3 Hz, 1H), 3.04-2.81 (m, 3H), 2.47-2.31 (m, 3H), 2.23-1.98 (m, 4H), 1.92-1.83 (m, 1H), 1.67-1.34 (m, 2H), 1.34-1.21 (m, 1H), 1.13 (s, 9H)。

step b:

Stirring at room temperature (4R) (2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid (64 mg, 0.44 mmol) and HATU (0.17 g, 0.45 mmol) in DMF (2 mL) was addedS)-N-[(R) - (5-chloro-4-cyclobutyl-2-methoxyphenyl) (piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.12 g, 0.29 mmol) and Et₃N (88 mg, 0.87 mmol). The resulting solution was stirred at room temperature for 30 minutes. The resulting solution was quenched with water (50 mL) and extracted with EA (3X 40 mL). The combined organic layers were washed with brine (2X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 65% aqueous ACN (plus 0.05% TFA) to give (a) as a pale yellow oilS)-N-[(R) - (5-chloro-4-cyclobutyl-2-methoxyphenyl) ([1- [ ((ii) a4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide (50 mg, 38%); c₂₇H₄₁ClN₂O₅S [M + H]⁺Calculated lcms (esi): 541, 543 (3: 1), measured values 541, 543 (3: 1) and (S)-N-[(R) - (5-chloro-4-cyclobutyl-2-methoxyphenyl) ([1- [ ((ii) a2R) -2, 3-dihydroxypropanoyl group]Piperidin-4-yl radical]) Methyl radical]2-methylpropane-2-sulfinamide in the form of a pale yellow oil (30 mg, 25%): C₂₄H₃₇ClN₂O₅S[M + H]⁺Calculated lcms (esi): 501, 503 (3: 1), found 501, 503 (3: 1).

Step c:

stirring at room temperature (S)-N-[(R) - (5-chloro-4-cyclobutyl-2-methoxyphenyl) ([1- [ ((ii) a4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]2-methylpropane-2-sulfinamide (50 mg, 0.09 mmol) and (CS)-N-[(R) - (5-chloro-4-cyclobutyl-2-methoxyphenyl) ([1- [ ((ii) a2R) -2, 3-dihydroxypropanoyl group]Piperidin-4-yl radical]) Methyl radical]To a solution of (2-methylpropane-2-sulfinamide) (30 mg, 0.06 mmol) in DCM (2 mL) was added BBr₃(0.14 g, 0.55 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was quenched with MeOH (1 mL) at 0 deg.C and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Prep C18 OBD column, 5 μm, 19X 150 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 5% B to 45% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.62 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure, and yielded compound 288 as an off-white solid (a mixture of (a), (b), (c), and (d))2R)-1-[4-[(R) -amino (5-chloro-4-cyclobutyl-2-hydroxyphenyl) methyl group]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid) (28.3 mg, 25% of two steps in total) C₁₉H₂₇ClN₂O₄ [M + H]⁺Calculated lcms (esi): 383, 385 (3: 1), measured 383, 385 (3: 1); ¹H NMR (400 MHz, CD₃OD) δ 7.22 (s, 1H), 6.94 (s, 1H), 4.70-4.38 (m, 2H), 4.32-4.03 (m, 2H), 3.87-3.56 (m, 3H), 3.19-2.92 (m, 1H), 2.67 (dt, J =45.2, 12.8 Hz, 1H), 2.48-2.29 (m, 3H), 2.19-1.93 (m, 4H), 1.93-1.80 (m, 1H), 1.48-1.06 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -76.99.

Example 228 Compound 289 ((2)R)-1-[4-[(R) -amino (5-chloro-4-cyclopropyl-2-hydroxyphenyl) methyl group]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one)

Step a:

to a stirred solution of 1-bromo-5-chloro-4-cyclopropyl-2- (prop-2-en-1-yloxy) benzene (intermediate 72, example 72) (0.1 g, 0.43 mmol) in THF (3 mL) at-78 deg.C under a nitrogen atmosphere was added dropwisenBuLi (0.17 mL, 0.43 mmol, 2.5M in hexane). The reaction was stirred at-78 ℃ for 30 minutes. Then add (A) over 10 minutesS)-N-[[1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]Methylene group]2-methylpropane-2-sulfinamide (0.10 g, 0.29 mmol). The resulting solution was stirred at-78 ℃ for 2 hours. Reacting with saturated NH₄Aqueous Cl (1 mL) was quenched. The mixture was diluted with water (30 mL). The resulting mixture was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 62% aqueous ACN (plus 0.01% TFA) to give (b) (as a colorless oil)S)-N-[(S) - [ 5-chloro-4-cyclopropyl-2- (prop-2-en-1-yloxy) phenyl]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical ]) Methyl radical]2-methylpropane-2-sulfinamide (30 mg, 19%): C₂₈H₄₁ClN₂O₅S [M + H]⁺Calculated lcms (esi): 553, 555 (3: 1), found 553, 555 (3: 1);¹H NMR (400 MHz, CD₃OD) δ 7.28 (d, J = 3.2 Hz, 1H), 6.55 (s, 1H), 6.16-6.00 (m, 1H), 5.49-5.23 (m, 2H), 4.83-4.77 (m, 1H), 4.62-4.35 (m, 4H), 4.32-4.01 (m, 3H), 3.16-2.87 (m, 1H), 2.69-2.53 (m, 2H), 2.27-1.99 (m, 3H), 1.45-1.22 (m, 8H), 1.14 (d, J = 6.7 Hz, 9H), 1.05-0.98 (m, 2H), 0.76-0.66 (m, 2H)。

step b:

stirring under nitrogen atmosphere at room temperatureS)-N-[(R) - [ 5-chloro-4-cyclopropyl-2- (prop-2-en-1-yloxy) phenyl]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide (35 mg, 0.06 mmol) and Pd (PPh)₃)₄(4 mg) to a mixture in THF (1 mL) was added NaBH₄(5 mg, 0.13 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. Will react with H₂O (2 mL) quench. Concentrating the obtained mixture under reduced pressure to obtain (A) as brown solidS)-N-[(R) - (5-chloro-4-cyclopropyl-2-hydroxyphenyl) ([1- [ (4) ]R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]2-methylpropane-2-sulfinamide (35 mg, crude): C₂₅H₃₇ClN₂O₅S [M + H]⁺Calculated lcms (esi): 513, 515 (3: 1), found 513, 515 (3: 1);

step c:

stirring at room temperature (S)-N-[(R) - (5-chloro-4-cyclopropyl-2-hydroxyphenyl) ([1- [ (4) ]R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide (35 mg, 0.07 mmol) in THF (1 mL) aqueous HCl (4) was added N0.5 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column 19X 15 mm, 5 μm; mobile phase A: having a NH concentration of 10 mmol/L₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 5% B to 30% B in 7 minutes; a detector: UV 254/220 nm; retention time: 5.03 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure to give compound 289 ((2) as an off-white solidR)-1-[4-[(R) -amino (5-chloro-4-cyclopropyl-2-hydroxyphenyl) methyl group]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one) (11 mg, 44%): C₁₈H₂₅ClN₂O₄ [M + H]⁺Calculated lcms (esi): 369, 371 (3: 1), found 369, 371 (3: 1);¹H NMR (400 MHz, CD₃OD) 7.10 (s, 1H), 6.38 (s, 1H), 4.67-4.47 (m, 2H), 4.11 (dd, J = 47.7, 13.8 Hz, 1H), 3.89-3.81 (m, 1H), 3.74-3.54 (m, 2H), 3.13-2.93 (m, 1H), 2.69-2.56 (m, 1H), 2.20-1.95 (m, 3H), 1.53-1.39 (m, 1H), 1.40-1.11 (m, 2H), 1.06-0.84 (m, 2H), 0.70-0.53 (m, 2H)。

example 229. Compound 290 (2)R) -1- [4- [ amino (4, 5-dichloro-3-fluoro-2-hydroxyphenyl) methyl group]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid

Step a:

to a stirred solution of 1-bromo-4, 5-dichloro-3-fluoro-2- (prop-2-en-1-yloxy) benzene (intermediate 46, example 46) (0.80 g, 2.67 mmol) in THF (6 mL) at 0 deg.C under a nitrogen atmosphere was added dropwisei-PrMgCl (1.60 mL, 3.20 mmol, 2M in THF). After stirring at 0 ℃ for 30 minutes under nitrogen, a solution of tert-butyl 4-formylpiperidine-1-carboxylate (0.62 g, 2.93 mmol) in THF (4 mL) was added dropwise at 0 ℃ under nitrogen. The resulting mixture was allowed to warm to room temperature and stirred at room temperature under nitrogen atmosphere for 2 hours. Reacting with saturated NH ₄Aqueous Cl (20 mL) was quenched and extracted with EA (2X 10 mL). Passing the organic phase over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography, eluting with PE/EA (1/1), to obtain 4- [ [4, 5-dichloro-3-fluoro-2- (prop-2-en-1-yloxy) phenyl ] as colorless oil](hydroxy) methyl group]Piperidine-1-carboxylic acid tert-butyl ester (0.55 g, 48%): C₂₀H₂₆Cl₂FNO₄ [M + H - 100]⁺Calculated lcms (esi): 334, 336 (3: 2), found 334, 336 (3: 2).

Step b:

to 4- [ [4, 5-dichloro-3-fluoro-2- (prop-2-en-1-yloxy) phenyl group at 0 ℃](hydroxy) methyl group]To a solution of tert-butyl piperidine-1-carboxylate (0.55 g, 1.27 mmol) in DCM (10 mL) was added dess-martin reagent (0.81 g, 1.90 mmol). The reaction was then stirred at room temperature for 2 hours. The mixture obtained is treated with a cosolvent NaHCO₃Aqueous solution/Na₂SO₃Dissolving in waterLiquid (20 mL, v/v = 1/1) wash. The organic phase was washed with brine, over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with PE/EA (1/1) to give 4- [4, 5-dichloro-3-fluoro-2- (prop-2-en-1-yloxy) benzoyl group as a pale yellow oil]Piperidine-1-carboxylic acid tert-butyl ester (0.50 g, 91%): C₂₀H₂₄Cl₂FNO₄ [M + H - 56]⁺Calculated lcms (esi): 376, 378 (3: 2), measured 376, 378 (3: 2); ¹H NMR (400 MHz, CDCl₃) δ 7.40 (d, J = 2.1 Hz, 1H), 6.08-5.95 (m, 1H), 5.46-5.30 (m, 2H), 4.75-4.67 (m, 2H), 4.11 (s, 2H), 3.28-3.20 (m, 1H), 2.84 (t, J = 12.4 Hz, 2H), 1.85 (d, J = 12.9 Hz, 2H), 1.67-1.53 (m, 2H), 1.48 (d, J = 1.8 Hz, 9 H)。

Step c:

to a stirred 4- [4, 5-dichloro-3-fluoro-2- (prop-2-en-1-yloxy) benzoyl group under nitrogen atmosphere]To a solution of piperidine-1-carboxylic acid tert-butyl ester (0.50g, 1.16 mmol) and 2-methylpropane-2-sulfinamide (0.28 g, 2.31 mmol) in THF (20 mL) was added Ti (OEt) in one portion₄(2.64 g, 11.57 mmol). The reaction solution was stirred at 80 ℃ for 30 hours under nitrogen atmosphere. After cooling to room temperature, the resulting solution was taken up in saturated NaHCO₃Aqueous solution (60 mL) was quenched. The resulting mixture was filtered. The filtrate was extracted with EA (2X 20 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 4- [ [4, 5-dichloro-3-fluoro-2- (prop-2-en-1-yloxy) phenyl ] in the form of a pale yellow oil][ (2-methylpropane-2-sulfinyl) imino]Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester (0.80 g, crude): C₂₄H₃₃Cl₂FN₂O₄S [M + H - 100]⁺Calculated lcms (esi): 435, 437 (3: 2), found 435, 437 (3: 2).

Step d:

4- [ [4, 5-dichloro-3-fluoro-2- (prop-2-en-1-yloxy) phenyl ] stirred at 0 ℃ under a nitrogen atmosphere][ (2-methylpropane-2-sulfinyl) imino]Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester (0.80 g, 2.2)4 mmol) in MeOH (10 mL) NaBH was added portionwise ₄(0.17 g, 4.48 mmol). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The mixture is treated with NH₄Aqueous Cl (40 mL) was quenched and concentrated to remove MeOH. The aqueous layer was then extracted with EA (2X 30 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 4- [ [4, 5-dichloro-3-fluoro-2- (prop-2-en-1-yloxy) phenyl ] in the form of a pale yellow oil][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester (0.80 g, crude): C₂₄H₃₅Cl₂FN₂O₄S [M + H - 100]⁺Calculated lcms (esi): 437, 439 (3: 2), found 437, 439 (3: 2).

Step e:

to a stirred 4- [ [4, 5-dichloro-3-fluoro-2- (prop-2-en-1-yloxy) phenyl group at room temperature][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]To a solution of tert-butyl piperidine-1-carboxylate (0.80 g, crude) in DCM (8 mL) was added TFA (2 mL). The reaction solution was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction mixture was washed with saturated NaHCO₃The aqueous solution was neutralized to pH 8. The resulting mixture was extracted with DCM (3X 25 mL). The combined organic layers were washed with brine (10 mL) and Na₂SO₄And (5) drying. Filtering, concentrating the filtrate under reduced pressure to obtain light yellow oil N- [ [4, 5-dichloro-3-fluoro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.60 g, crude): C₁₉H₂₇Cl₂FN₂O₂S [M + H]⁺Calculated lcms (esi): 437, 439 (3: 2), found 437, 439 (3: 2).

Step f:

to a stirred solution of (4R) -2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid (0.13 g, 0.89 mmol) and HATU (0.39 g, 1.03 mmol) in DMF (8 mL) under a nitrogen atmosphere was addedN- [ [4, 5-dichloro-3-fluoro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.60 g, crude) and Et₃N (0.48 mL, 4.71 mmol). In thatThe reaction solution was stirred at room temperature for 2 hours under nitrogen atmosphere. The resulting solution was poured into water (50 mL). The resulting mixture was extracted with EA (2X 20 mL). The organic layer was washed with brine (5X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. Filtering, concentrating the filtrate under reduced pressure to obtain light yellow oilN- [ [4, 5-dichloro-3-fluoro-2- (prop-2-en-1-yloxy) phenyl]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]2-methylpropane-2-sulfinamide (0.50 g, crude): C₂₅H₃₅Cl₂FN₂O₅S [M + H]⁺Calculated lcms (esi): 565, 567 (3: 2), found 565, 567 (3: 2).

Step g:

under nitrogen atmosphere at room temperature with stirringN- [ [4, 5-dichloro-3-fluoro-2- (prop-2-en-1-yloxy) phenyl]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide (0.50 g, crude) and Pd (PPh)₃)₄(20 mg, 0.02 mmol) in THF (6 mL) was added NaBH in portions₄(0.13 g, 3.54 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was saturated with NH at 0 deg.C₄Aqueous Cl (3 mL) was quenched and concentrated under reduced pressure to give a pale yellow oilN- [ (4, 5-dichloro-3-fluoro-2-hydroxyphenyl) ([1- [ (4) ]R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]2-methylpropane-2-sulfinamide (0.50 g, crude): C₂₂H₃₁Cl₂FN₂O₅S [M + H]⁺Calculated lcms (esi): 525, 527 (3: 2), found 525, 527 (3: 2).

Step h:

at room temperature with stirringN- [ (4, 5-dichloro-3-fluoro-2-hydroxyphenyl) ([1- [ (4) ]R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide (0.50 g, crude) to a mixture in THF (3 mL) aqueous HCl (6) was added dropwiseN,3 mL)). The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was subjected to preparative HPLC on the following strips Purifying under the condition of: column: xselect CSH OBD column, 30 × 150 mm, 5 μm; mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 5% B to 22% B in 7 minutes; a detector: 220 nm; retention time: 6.48 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 290 ((2) as an off-white solidR) -1- [4- [ amino (4, 5-dichloro-3-fluoro-2-hydroxyphenyl) methyl group]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid) (55.9 mg, 10% of the total of 6 steps): C₁₅H₁₉Cl₂FN₂O₄ [M + H]⁺Calculated lcms (esi): 381, 383 (3: 2), found 381, 383 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.34 (s, 1H), 4.72-4.41 (m, 2H), 4.32-4.03 (m, 2H), 3.77-3.56 (m, 2H), 3.08 (dt, J = 44.1, 12.7 Hz, 1H), 2.67 (dt, J = 44.2, 12.9 Hz, 1H), 2.38-2.35 (m, 1H), 2.02 (d, J = 12.8 Hz, 1H), 1.50-1.16 (m, 3H)； ¹⁹F NMR (376 MHz, CDCl₃) δ -77.014, -132.61.

EXAMPLE 230 Compound 292 ((2)R)-1-[4-[(R) -amino (5-chloro-4-ethyl-2-hydroxyphenyl) methyl group]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid)

Step a:

to a stirred solution of 1-bromo-5-chloro-4-ethyl-2- (prop-2-en-1-yloxy) benzene (intermediate 57, example 57) (0.24 g, 0.87 mmol) in THF (4 mL) at-78 deg.C under a nitrogen atmosphere was addedn-BuLi (0.34 mL, 0.85 mmol, 2.5M in hexane). The solution was stirred at-78 ℃ for 30 minutes. Then will (S)-N-([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]A solution of methylene) -2-methylpropane-2-sulfinamide (0.20 g, 0.58 mmol) in THF (2 mL) was added to the solution. The reaction was stirred at-78 ℃ for 2 hours. Reacting with saturated NH ₄Aqueous Cl (1 mL) was quenched and diluted with water (30 mL). The aqueous layer was extracted with EA (3X 30 mL). Combining the organic mattersThe layer was washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 65% aqueous ACN (plus 0.05% TFA) to give (b) as a colorless oilS)-N-[(R) - [ 5-chloro-4-ethyl-2- (prop-2-en-1-yloxy) phenyl]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]2-methylpropane-2-sulfinamide (0.15 g, 48%): C₂₇H₄₁ClN₂O₅S [M + H]⁺Calculated lcms (esi): 541, 543 (3: 1), measured value 541, 543 (3: 1);¹H NMR (400 MHz, CD₃OD) δ 7.31-7.20 (m, 1H), 6.92 (s, 1H), 6.19-5.97 (m, 1H), 5.37-5.23 (m, 2H), 4.76-4.47 (m, 4H), 4.36-3.97 (m, 2H), 3.79-3.57 (m, 2H), 3.20-2.83 (m, 1H), 2.82-2.39 (m, 3H), 2.30-2.03 (m, 2H), 1.44-1.35 (m, 6H), 1.35-1.29 (m, 2H), 1.29-1.19 (m, 3H), 1.16-1.11 (m, 10H)。

step b:

stirring at room temperature (S)-N-[(R) - [ 5-chloro-4-ethyl-2- (prop-2-en-1-yloxy) phenyl]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide (0.15 g, 0.28 mmol) and Pd (PPh)₃)₄(3 mg, 0.003 mmol) in THF (5 mL) NaBH was added₄(21 mg, 0.55 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The reaction was quenched with saturated NH at room temperature₄Aqueous Cl (0.5 mL) was quenched. Concentrating the obtained mixture under reduced pressure to obtain (A) in the form of yellow oilS)-N-[(R) - (5-chloro-4-ethyl-2-hydroxyphenyl) ([1- [ (4) ] R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl]) Methyl radical]2-methylpropane-2-sulfinamide (0.15 g, crude), which was used in the next step without further purification: c₂₄H₃₇ClN₂O₅S [M + H]⁺Calculated lcms (esi): 501, 503 (3: 1), found 501, 503 (3: 1).

Step c:

stirring at room temperature (S)-N-[(R) - (5-chloro-4-ethyl)-2-hydroxyphenyl) ([1- [ (4)R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical](iii) -2-methylpropane-2-sulfinamide (0.15 g, 0.30 mmol) in 1, 4-dioxane (1 mL) to which was added aqueous HCl (4)N,1 mL). The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: a Xselect CSH OBD column 30 × 150 mm 5 μm n; mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 7% B to 25% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.34 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to afford compound 292 ((2) as an off-white solidR)-1-[4-[(R) -amino (5-chloro-4-ethyl-2-hydroxyphenyl) methyl group]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one) trifluoroacetic acid (23 mg, 18% of two steps in total): C ₁₇H₂₅ClN₂O₄ [M + H]⁺Lcms (esi) calculated value of (a): 357, 359 (3: 1), found 357, 359 (3: 1);¹H NMR (400 MHz, CD₃OD) δ 7.25 (s, 1H), 6.86 (s, 1H), 4.66-4.47 (m, 2H), 4.29-4.04 (m, 2H), 3.69-3.55 (m, 2H), 3.16-3.01 (m, 1H), 2.79-2.54 (m, 3H), 2.48-2.26 (m, 1H), 2.08-1.91 (m, 1H), 1.41-1.18 (m, 6H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -76.96.

example 231 Compound 293 ((2)R)-1-[4-[(R) -amino (2-hydroxy-4, 5-dimethylphenyl) methyl]Piperidin-1-yl]-2, 3-dihydroxypropan-1-one trifluoroacetic acid)

Step a:

to a stirred solution of 2-bromo-4, 5-dimethylphenol (2.00 g, 9.94 mmol) in DMF (10 mL) at room temperature was added 3-bromoprop-1-ene (1.81 g, 14.92 mmol) and K₂CO₃(2.75 g, 19.89 mmol). The reaction was stirred at 40 ℃ for 16 hours. The reaction was diluted with water (50 mL). The resulting mixture was extracted with EA (3X 20 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE to give 1-bromo-4, 5-dimethyl-2- (prop-2-en-1-yloxy) benzene (1.29 g, 54%) as a grey white oil:¹H NMR (400 MHz, CD₃OD) δ 7.28 (s, 1H), 6.82 (s, 1H), 6.15-6.00 (m, 1H), 5.53-5.42 (m, 1H), 5.31-5.20 (m, 1H), 4.70-4.45 (m, 2H), 2.21 (d, J = 16.0 Hz, 6H)。

step b:

to a stirred solution of 1-bromo-4, 5-dimethyl-2- (prop-2-en-1-yloxy) benzene (0.10 g, 0.43 mmol) in THF (3 mL) at-78 deg.C under a nitrogen atmosphere was added dropwisenBuLi (0.18 mL, 0.450 mmol, 2.5M in hexane). The reaction was stirred at-78 ℃ for 30 minutes. Then adding (S)-N-[[1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl ]Piperidin-4-yl]Methylene group]-2-methylpropane-2-sulfinamide (0.10 g, 0.29 mmol). The resulting solution was stirred at-78 ℃ for 1 hour. Saturated NH is used for reaction₄Aqueous Cl (1 mL) was quenched. The resulting mixture was diluted with EA (20 mL) and water (20 mL), and the aqueous layer was extracted with EA (3X 20 mL). The combined organic layers were washed with brine (3X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC, eluting with PE/EA (1/4), to give (a) as a colorless oilS)-N-[(S)-[1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical][4, 5-dimethyl-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]-2-methylpropane-2-sulfinamide (42 mg, 29%): C₂₇H₄₂N₂O₅S [M + H]⁺Calculated lcms (esi): 507, found 507;¹H NMR (400 MHz, CD₃OD) δ 7.00 (d, J = 5.2 Hz, 1H), 6.78 (s, 1H), 6.21-6.06 (m, 1H), 5.44 (d, J = 16.8 Hz, 1H), 5.29 (d, J =10.5 hours z, 1H), 4.85-4.78 (m, 1H), 4.56 (d,J = 5.0 Hz, 2H), 4.47-4.33 (m, 1H), 4.29-4.00 (m, 4H), 3.17-2.87 (m, 1H), 2.73-2.53 (m, 1H), 2.25 (s, 3H), 2.21 (s, 3H), 2.15-2.01 (m, 2H), 1.42-1.33 (m, 7H), 1.30-1.24 (m, 2H), 1.15-1.05 (m, 9H)。

step c:

stirring under nitrogen atmosphere at room temperatureS)-N-[(R)-[1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical][4, 5-dimethyl-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]-2-methylpropane-2-sulfinamide (43 mg, 0.08 mmol) and Pd (PPh)₃)₄(5 mg, 0.01 mmol) to a mixture in THF (1 mL) was added NaBH₄(6 mg, 0.16 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. Reaction with H at room temperature ₂O (30 mL) was quenched. The resulting mixture was extracted with EA (3X 20 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give (a) as a brown solidS)-N-[(R)-[1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical](2-hydroxy-4, 5-dimethylphenyl) methyl]2-methylpropane-2-sulfinamide (43 mg, crude): C₂₄H₃₈N₂O₅S [M + H]⁺Calculated lcms (esi): 467, found 467.

Step d:

at room temperature with stirringN-[(R)-[1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical](2-hydroxy-4, 5-dimethylphenyl) methyl]-2, 2-Dimethylpropionamide (43 mg, 0.09 mmol) in THF (1 mL) aqueous HCl (4) is added dropwiseN0.50 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column 19X 150 mm, 5 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 5% B to 30% B in 7 minutes; a detector: UV 254/220 nm; retention time: 5.03 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure to give compound 293 ((2) as an off-white solid R)-1-[4-[(R) -amino (2-hydroxy-4, 5-dimethylphenyl) methyl]Piperidin-1-yl]-2, 3-dihydroxypropan-1-one trifluoroacetic acid) (11 mg, 25% in two steps) C₁₇H₂₆N₂O₄ [M + H]⁺Lcms (esi) calculated value of (a): 323, found 323;¹H NMR (400 MHz, CD₃OD) δ 6.94 (s, 1H), 6.71 (s, 1H), 4.72-4.41 (m, 2H), 4.31-3.98 (m, 2H), 3.78-3.57 (m, 2H), 3.15-2.97 (m, 1H), 2.66 (dt, J = 50.5, 13.3 Hz, 1H), 2.48-2.30 (m, 1H), 2.21 (d, J = 7.7 Hz, 6H), 2.10-1.88 (m, 1H), 1.45-1.09 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.02.

example 232 Compound 294 ((2)R)-1-[4-[(R) -amino (2-hydroxy-4-methylphenyl) methyl]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid)

Step a:

to a stirred solution of 1-bromo-4-methyl-2- (prop-2-en-1-yloxy) benzene (intermediate 53, example 53) (99 mg, 0.44 mmol) in THF (3 mL) at-78 deg.C under a nitrogen atmosphere was added dropwisen-BuLi (0.17 mL, 0.425 mmol, 2.5M n-hexane solution). The reaction was stirred at-78 ℃ for 30 minutes. Then will (S)-N-[[1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]Methylene group]-2-methylpropane-2-sulfinamide (0.10 g, 0.29 mmol) was added to the reaction. The resulting solution was stirred at-78 ℃ for 1 hour. Reacting with saturated NH₄Aqueous Cl (1 mL) was quenched at-78 ℃. The resulting mixture was diluted with EA (30 mL) and water (30 mL), and the aqueous layer was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC, eluting with PE/EA (1/4), to give (a) as a colorless oil S)-N-[(R)-[1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical][ 4-methyl-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]2-methylpropane-2-sulfinamide (35 mg, 24%): C₂₆H₄₀N₂O₅S [M + H]⁺Calculated lcms (esi): 493, found 493.

Step b:

stirring at room temperature (S)-N-[(R)-[1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical][ 4-methyl-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]-2-methylpropane-2-sulfinamide (30 mg, 0.06 mmol) and Pd (PPh)₃)₄ (0.70 mg, 0.001 mmol) in THF (0.5 mL) NaBH was added₄ (5 mg, 0.12 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated NH at room temperature₄Aqueous Cl (0.5 mL) was quenched. Concentrating the obtained mixture under reduced pressure to obtain (A) in the form of yellow oilS)-N-[(R)-[1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical](2-hydroxy-4-methylphenyl) methyl group]2-methylpropane-2-sulfinamide (20 mg, crude), which was used directly in the next step without further purification. C₂₃H₃₆N₂O₅S [M + H]⁺Calculated lcms (esi): 453, found 453.

Step c:

stirring at room temperature (S)-N-[(R)-[1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical](2-hydroxy-4-methylphenyl) methyl group ](iii) -2-methylpropane-2-sulfinamide (30 mg, 0.07 mmol) in 1, 4-dioxane (1 mL) to which was added aqueous HCl (4)N,0.5 mL). The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge Prep C18 OBD column, 5 μm, 19 × 150 mm; mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 2% B to 18% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.00 minutes. Fractions containing the desired product were collected and concentrated under reduced pressure to give compound 294 ((2) as a brown oilR)-1-[4-[(R) -amino (2-hydroxy-4-methylphenyl) methyl]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid) (4 mg, 15% in two steps total) C₁₆H₂₄N₂O₄ for [M + H]⁺Calculated lcms (esi): 309, measured value 309;¹H NMR (400 MHz, CD₃OD) δ 7.07 (d, J = 7.6 Hz, 1H), 6.74 (d, J = 7.1 Hz, 2H), 4.68-4.40 (m, 2H), 4.30-4.01 (m, 2H), 3.78-3.52 (m, 2H), 3.07 (dt, J = 50.3, 10.9 Hz, 1H), 2.66 (dt, J = 50.7, 12.8 Hz, 1H), 2.49-2.33 (m, 1H), 2.30 (s, 3H), 2.03 (t, J = 10.4 Hz, 1H), 1.53-0.99 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -76.96.

example 233 Compound 295 ((2)R)-1-[4-[(R) -amino (5-chloro-2-hydroxyphenyl) methyl group]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one)

Step a:

to a stirred solution of 2-bromo-4-chloro-1-methoxybenzene (96 mg, 0.44 mmol) in THF (3 mL) at-78 deg.C under a nitrogen atmosphere was addednBuLi (0.17 mL, 0.43 mmol, 2.5M in hexane). The reaction was stirred at-78 ℃ for 30 minutes. Then will ( S)-N-[[1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]Methylene group]-2-methylpropane-2-sulfinamide (0.10 g, 0.29 mmol) was added to the reaction. The resulting solution was stirred at-78 ℃ for 1 hour. Reacting with saturated NH₄Aqueous Cl (2 mL) was quenched. The resulting mixture was diluted with EA (30 mL) and water (30 mL), and the aqueous layer was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC, eluting with PE/EA (1/4) to give (A) as a pale yellow oilS)-N-[(R) - (5-chloro-2-methoxyphenyl) ([1- [ (4)R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]2-methylpropane-2-sulfinamide (55 mg, 52%): C₂₃H₃₅ClN₂O₅S [M + H]⁺Calculated lcms (esi): 487, 489 (3: 1), found 487, 489 (3: 1);¹H NMR (400 MHz, CDCl₃) δ 7.27-7.20 (m, 1H), 7.10 (s, 1H), 6.89-6.80 (m, 1H), 4.74-4.59 (m, 1H), 4.60-4.40 (m, 2H), 4.38-4.05 (m, 1H), 3.97-3.69 (m, 4H), 3.68-3.50 (m, 1H), 3.15-2.46 (m, 2H), 2.31-2.21 (m, 1H), 2.04-1.94 (m, 1H), 1.55-1.21 (m, 9H), 1.21-1.11 (m, 9H)。

step b:

at 0 ℃ under (S)-N-[(R) - (5-chloro-2-methoxyphenyl) ([1- [ (4)R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]To a solution of (2-methylpropane-2-sulfinamide) (60 mg, 0.12 mmol) in DCM (2 mL) was added BBr₃(93 mg, 0.37 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction was quenched with water (2 mL) at 0 ℃. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column 30X 150 mm, 5 μm; mobile phase A: having a NH concentration of 10 mmol/L ₄HCO₃Water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 20% B to 40% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.43 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure to give compound 295 (2) as an off-white solidR)-1-[4-[(R) -amino (5-chloro-2-hydroxyphenyl) methyl group]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one (11 mg, 28%): C₁₅H₂₁ClN₂O₄ [M + H]⁺Calculated lcms (esi): 329, 331 (3: 1), found 329, 331 (3: 1);¹H NMR (400 MHz, CD₃OD) δ 7.33-7.18 (m, 2H), 6.91 (d, J = 9.1 Hz, 1H), 4.69-4.45 (m, 2H), 4.29-4.05 (m, 2H), 3.77-3.56 (m, 2H), 3.08 (dt, J = 45.2, 12.6 Hz, 1H), 2.67 (dt, J = 45.8, 13.0 Hz, 1H), 2.46-2.31 (m, 1H), 2.09-1.96 (m, 1H), 1.50-1.08 (m, 3H)。

EXAMPLE 234 Compound 297 (4- [4- [ (R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl ] piperidin-1-yl ] -1-methylpyridin-2-one)

Step a:

under nitrogenUnder an atmosphere at room temperature to stirring (S)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl](iii) -2-methylpropane-2-sulfinamide (0.20 g, 0.48 mmol) and 4-bromo-1-methylpyridin-2-one (0.27 g, 1.43 mmol) in toluene (2 mL) to which was added Pd (OAc)₂(11 mg, 0.05 mmol), BINAP (30 mg, 0.05 mmol) andtBuONa (0.14 g, 1.43 mmol). The reaction was degassed three times with nitrogen and stirred under nitrogen at 100 ℃ for 24 hours. After cooling to room temperature, the reaction was diluted with EA (30 mL) and water (30 mL). The aqueous solution was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 10 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 40% aqueous ACN (plus 0.05% TFA) to give (a) as a yellow oilS)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) [1- (1-methyl-2-oxopyridin-4-yl) piperidin-4-yl]Methyl radical]-2-methylpropane-2-sulfinamide (70 mg, 50%): C₂₂H₂₉Cl₂N₃O₃S [M + H]⁺Calculated lcms (esi): 486, 488 (3: 2), found 486, 488 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.39-7.30 (m, 2H), 6.94 (s, 1H), 6.24 (dd, J = 7.8, 2.8 Hz, 1H), 5.72 (d, J = 2.8 Hz, 1H), 4.40 (d, J = 9.0 Hz, 1H), 3.99 (d, J = 13.4 Hz, 1H), 3.87 (d, J = 13.3 Hz, 1H), 3.44 (s, 3H), 2.97-2.76 (m, 2H), 2.22 (d, J = 13.5 Hz, 1H), 2.15-2.05 (m, 1H), 1.50-1.31 (m, 3H), 1.14 (s, 9H)。

step b:

stirring at room temperature (S)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) [1- (1-methyl-2-oxopyridin-4-yl) piperidin-4-yl]Methyl radical](iii) -2-methylpropane-2-sulfinamide (70 mg, 0.14 mmol) in 1, 4-dioxane (2 mL) to which was added aqueous HCl (4)N1 mL). The reaction solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Prep C18 OBD column, 5 μm, 19X 150 mm; mobile phase A: has 10 mmoL/L NH₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 15% B to 50% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.17 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure, and provided compound 297 (4- [4- [ (R)) R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidin-1-yl]-1-methylpyridin-2-one) (30 mg, 55%): C₁₈H₂₁Cl₂N₃O₂ [M + H]⁺Calculated lcms (esi): 382, 384 (3: 2), found 382, 384 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.37 (d, J = 7.7 Hz, 1H), 7.22 (s, 1H), 6.87 (s, 1H), 6.23 (dd, J = 7.8, 2.8 Hz, 1H), 5.72 (d, J = 2.8 Hz, 1H), 4.03-3.95 (m, 1H), 3.95-3.83 (m, 2H), 3.44 (s, 3H), 2.97-2.76 (m, 2H), 2.11-1.96 (m, 2H), 1.53-1.42 (m, 1H), 1.42-1.23 (m, 2H)。

EXAMPLE 235 Compound 298 (5- [4- [ (()R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]-1-methylpyrazine-2-one trifluoroacetic acid)

Step a:

to a stirred mixture of 4-methyl-5-oxopyrazine-2-carboxylic acid (44 mg, 0.28 mmol) and HATU (0.14 g, 0.36 mmol) in DMF (2 mL) at room temperature was added: (S)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.10 g, 0.24 mmol) and Et₃N (85 mg, 0.84 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EA (3X 20 mL). The combined organic layers were washed with brine (2X 15 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give (A) as a pale gray solidS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (4-methyl-5-oxopyrazine-2-carbonyl) piperidin-4-yl group]Methyl radical]-2-methylpropane-2-sulfinamide (0).11 g, 80%): C₂₅H₃₂Cl₂N₄O₄S [M + H]⁺Calculated lcms (esi): 555, 557 (3: 2), found 555, 557 (3: 2).

Step b:

under nitrogen atmosphere, at room temperature toS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (4-methyl-5-oxopyrazine-2-carbonyl) piperidin-4-yl]Methyl radical](ii) -2-methylpropane-2-sulfinamide (80 mg, 0.07 mmol) in HOAc (2 mL) Pd (PPh) was added₃)₄ (66 mg, 0.03 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 50% aqueous ACN (plus 0.1% TFA) to give (a) as a pale yellow oilS)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) [1- (4-methyl-5-oxopyrazine-2-carbonyl) piperidin-4-yl]Methyl radical]-2-methylpropane-2-sulfinamide (80 mg, 80%): C₂₂H₂₈Cl₂N₄O₄S [M + H]⁺Calculated lcms (esi): 515, 517, (3: 2), found 515, 517, (3: 2).

Step c:

stirring at room temperature (S)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) [1- (4-methyl-5-oxopyrazine-2-carbonyl) piperidin-4-yl]Methyl radical](iii) -2-methylpropane-2-sulfinamide (80 mg, 0.16 mmol) in 1, 4-dioxane (2 mL) to which was added aqueous HCl (4)N1 mL). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column X Bridge Prep C18 OBD column, 5 μm, 19X 150 mm; mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 10% B to 30% B in 7 minutes; a detector: UV 220/254 nm; retention time: 5.83 minutes. Collecting the fractions containing the desired product, concentrating under reduced pressure to obtain compound 298 (5- [4- [ (5- [)) as a pink solid R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]-1-methylpyrazin-2-one trifluoroacetic acid) (22 mg) C₁₈H₂₀Cl₂N₄O₃ [M + H]⁺Lcms (esi) calculated value of (a): 411, 413, (3: 2), found 411, 413, (3: 2);¹H NMR (400 MHz, CD₃OD) δ 8.06 (s, 1H), 7.98 (s, 1H), 7.44 (s, 1H), 7.08 (s, 1H), 4.68-4.25 (m, 2H), 4.19 (d, J = 9.7 Hz, 1H), 3.59 (s, 3H), 3.19-2.65 (m, 2H), 2.48-2.39 (m, 1H), 2.12-2.04 (m, 1H), 1.59-1.21 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.03.

in a manner analogous to that described for compound 298, fromS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]Starting with 2-methylpropane-2-sulfinamide and the corresponding acid (which is prepared as described herein, or is available from a commercial source), the compounds in table 1g below are prepared.

TABLE 1g

Example 236 Compound 299 (5- [4- [ (()R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]Piperidine-2-one trifluoroacetic acid

Step a:

to a stirred solution of 6-oxo-1, 6-dihydropyridine-3-carboxylic acid (109 mg, 0.79 mmol) in DMF (3 mL) at room temperature were added EDCI (0.20 g, 1.07 mmol) and HOBt (0.15 g, 1.07 mmol). Adding (to the mixture at room temperature)S)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide (0.30 g, 0.76 mmol) and Et₃N (0.14 g, 1.43 mmol). The resulting mixture was stirred at room temperature for 12 hours. The resulting mixture was washed with water (12 mL)And (6) diluting. The mixture was extracted with EA (3X 10 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give (A) as a yellow solidS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (6-oxo-1, 6-dihydropyridine-3-carbonyl) piperidin-4-yl group]Methyl radical]2-methylpropane-2-sulfinamide (0.25 g, crude): C₂₅H₃₁Cl₂N₃O₄S [M + H]⁺Calculated lcms (esi): 540, 542 (3: 2), found 540, 542 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.61 (s, 1H), 7.57-7.48 (m, 1H), 7.24 (s, 1H), 6.99 (s, 1H), 6.59 (d, J = 9.1 Hz, 1H), 6.11-5.96 (m, 1H), 5.48-5.34 (m, 2H), 4.58 (s, 2H), 4.48-4.07 (m, 2H), 2.98-2.68 (m, 2H), 2.21-1.97 (m, 2H), 1.53-1.39 (m, 2H), 1.37-1.25 (m, 2H), 1.16 (s, 9H)。

step b:

stirring under nitrogen atmosphere at room temperatureS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (6-oxo-1, 6-dihydropyridine-3-carbonyl) piperidin-4-yl group]Methyl radical]-2-methylpropane-2-sulfinamide (0.25 g, crude) and Pd (PPh)₃)₄(27 mg, 0.02 mmol) in THF (3 mL) NaBH was added₄(35 mg, 0.93 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. Subjecting the mixture to hydrogenation with hydrogen₂O (3 mL) was quenched at room temperature and concentrated under reduced pressure to give (A) as a brown yellow solidS)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) [1- (6-oxo-1, 6-dihydropyridine-3-carbonyl) piperidin-4-yl]Methyl radical]2-methylpropane-2-sulfinamide (0.25 g, crude): C₂₂H₂₇Cl₂N₃O₄S [M + H]⁺Calculated lcms (esi): 500, 502 (3: 2), found 500, 502 (3: 2).

Step c:

stirring at room temperature (S)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) [1- (6-oxo-1) H-pyridine-3-carbonyl) piperidin-4-yl]Methyl radical]-2-methylpropane-2-sulfinamide (0.25 g, 0.50 mmol) inTo a solution in THF (3 mL) was added dropwise an aqueous HCl solution (4)N1.5 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting with 45% aqueous ACN (plus 0.5% TFA). Collecting the fractions containing the desired product and concentrating under reduced pressure to obtain 5- [4- [ (R) ((R))R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]-1H-pyridin-2-one (0.18 g, 90%): C₁₈H₁₉Cl₂N₃O₃ [M + H]⁺Calculated lcms (esi): 396, 398 (3: 2), found 396, 398 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 8.08 (d, J = 14.0 Hz, 2H), 7.49 (s, 1H), 7.10 (s, 1H), 7.01 (d, J = 8.6 Hz, 1H), 4.69-3.72 (m, 3H), 3.05 (s, 2H), 2.55-2.36 (m, 1H), 2.14-1.95 (m, 1H), 1.64-1.21 (m, 3H)。

step d:

stirring 5- [4- [ (C) at room temperature under nitrogen atmosphereR) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]-1H-pyridin-2-one (0.18 g, 0.45 mmol) in MeOH (20 mL) and HCl (12)N2 mL) was added in portions to the mixture₂(90 mg, 0.40 mmol). The resulting mixture was stirred at room temperature under a hydrogen atmosphere (1.5 atm) for 2 hours. The resulting mixture was filtered and the filter cake was washed with MeOH (2X 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column 19X 150 mm, 5 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 8% B to 27% B in 7 minutes; a detector: UV 220 nm; retention time: 6.02 minutes. Collecting the fractions containing the desired product, concentrating under reduced pressure to obtain compound 299 (5- [4- [ (R)) R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]Piperidin-2-one trifluoroacetic acid) (40 mg, 17%): C₁₈H₂₃Cl₂N₃O₃ [M + H]⁺Calculated lcms (esi): 400, 402 (3: 2), found 400, 402 (3: 2); ¹H NMR (400 MHz, CD₃OD) δ 7.44 (d, J = 3.9 Hz, 1H), 7.09 (s, 1H), 4.59 (dd, J = 54.2, 13.5 Hz, 1H), 4.24-4.01 (m, 2H), 3.72-3.37 (m, 2H), 3.26-3.00 (m, 2H), 2.63 (dt, J = 44.4, 13.2 Hz, 1H), 2.50-2.29 (m, 3H), 2.14-1.82 (m, 3H), 1.51-1.04 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.12.

example 237 Compound 300(5- [4- [ (()R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]-1-methylpiperazin-2-one trifluoroacetic acid)

Step a:

stirring under nitrogen atmosphere at room temperatureS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1- (4-methyl-5-oxopyrazine-2-carbonyl) piperidin-4-yl group]Methyl radical]-2-methylpropane-2-sulfinamide (example 235, step a) (0.11 g, 0.20 mmol) and Pd (PPh)₃)₄(23 mg, 0.02 mmol) in THF (2 mL) NaBH was added₄(15 mg, 0.40 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction was quenched with saturated NH at room temperature₄Aqueous Cl solution was quenched. After 5 minutes, aqueous HCl (6) was added to the mixture at room temperatureN1.5 mL). After stirring at room temperature for an additional 30 minutes, the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column X Bridge Prep C18 OBD column, 5 μm, 19X 150 mm; mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 15% B to 35% B in 7 minutes; a detector: UV 220/254 nm; retention time: 5.89 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 300(5- [4- [ (5- [)) as an off-white solid R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]-1-methylpiperazin-2-one trifluoroacetic acid) (21 mg, 21%): C₁₈H₂₄Cl₂N₄O₃ [M + H]⁺Calculated lcms (esi): 415, 417 (3: 2), found 415, 417 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.45 (d, J =8.5 Hz, 1H), 7.10 (d, J = 3.5 Hz, 1H), 4.73-4.37 (m, 1H), 4.35-4.00 (m, 2H), 3.96-3.81 (d, J = 18.8 Hz, 2H), 3.81-3.46 (m, 2H), 3.16 (s, 2H), 3.06-2.99 (m, 3H), 2.93-2.60 (m, 1H), 2.52-2.35 (m, 1H), 2.18-2.02 (m, 1H), 1.54-1.41 (m, 1H), 1.40-1.07 (m, 2H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.08。

example 238 Compound 302 (, (R) -5- (4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) pyridin-2-ol)

Step a:

stirring at room temperature (S)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.30 g, 0.72 mmol), BINAP (45 mg, 0.072 mmol) andtto a solution of BuONa (0.14 g, 1.43 mmol) in toluene (5 mL) was added Pd₂(dba)₃Adduct CHCl₃(74 mg, 0.072 mmol) and 5-bromo-2-methoxypyridine (0.20 g, 1.5 equiv.). The reaction mixture was degassed three times with nitrogen and stirred at 120 ℃ for 12 hours under nitrogen. After cooling to room temperature, the resulting mixture was diluted with water (30 mL) and extracted with EA (2X 60 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 70% aqueous ACN (plus 0.05% TFA) to give (a) as a yellow oilS)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) [1- (6-methoxypyridin-3-yl) piperidin-4-yl ]Methyl radical]-2-methylpropane-2-sulfinamide (80 mg, 32%): C₂₂H₂₉Cl₂N₃O₃S [M + H]⁺Lcms (esi) calculated value of (a): 486, 488 (3: 2), found 486, 488 (3: 2).

Step b:

at room temperature toS)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) [1- (6-methoxypyridin-3-yl) piperidin-4-yl]Methyl radical]-2-Methylpropane-2-sulfinamide (20 mg, 0.04 mmol) in THF (2 mL) aqueous HCl (4) solution was added dropwiseN2 mL). The reaction solution was stirred at room temperature for 1 hour. Concentrating the obtained solution under reduced pressure to obtain crude product (A)R) -2- (amino (1- (6-methoxypyridin-3-yl) piperidin-4-yl) methyl) -4, 5-dichlorophenol. The crude product was used without further purification in the subsequent step: c₁₈H₂₁Cl₂N₃O₂ [M + H]⁺Calculated lcms (esi): 382, 384 (3: 2), found 382, 384 (3: 2).

Step c:

2- [ (iii)R) -amino [1- (6-methoxypyridin-3-yl) piperidin-4-yl]Methyl radical]A solution of (crude) 4, 5-dichlorophenol in HBr (60% HOAc solution, 1 mL) was stirred at 120 ℃ for 2 hours. After cooling to room temperature, the reaction solution was quenched with saturated NaHCO₃The aqueous solution was adjusted to pH 9. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Prep C18 OBD column, 5 μm, 19X 150 mm; mobile phase A: having a NH concentration of 20 mmol/L ₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 7% B to 25% B in 7 minutes; a detector: UV 220 nm; retention time: 7.85 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure and the compound 302 was obtained as a yellow oil (, (R) (R))R) -5- (4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidin-1-yl) pyridin-2-ol) (1.3 mg, 25% of two Steps taken in total): C₁₇H₁₉Cl₂N₃O₂ [M + H]⁺Calculated lcms (esi): 368, 370 (3: 2), found 368, 370 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.68 (dd, J = 9.7, 3.1 Hz, 1H), 7.48 (s, 1H), 7.10 (s, 1H), 7.00 (d, J = 3.0 Hz, 1H), 6.62 (d, J = 9.8 Hz, 1H), 4.24 (d, J = 9.8 Hz, 1H), 3.52 (d, J = 12.0 Hz, 1H), 3.31 (d, J = 12.0 Hz, 1H), 2.70-2.60 (m, 1H), 2.58-2.46 (m, 1H), 2.28-2.17 (m, 1H), 2.13-1.99 (m, 1H), 1.69-1.54 (m, 1H), 1.49-1.38 (m, 2H)。

example 239 compound 308 ((2R) -1- [ (3S) -3- [ amino (4, 5-dichloro-2-hydroxyphenyl) methyl ] pyrrolidin-1-yl ] -2, 3-dihydroxypropan-1-one isomer 1); compound 312 ((2R) -1- [ (3S) -3- [ amino (4, 5-dichloro-2-hydroxyphenyl) methyl ] pyrrolidin-1-yl ] -2, 3-dihydroxypropan-1-one isomer 2)

Step a:

to a stirred solution of 1-bromo-4, 5-dichloro-2- (prop-2-en-1-yloxy) benzene (example 6, step b) (2.73 g, 9.68 mmol) in THF (20 mL) at-10 deg.C under a nitrogen atmosphere was added dropwisei-PrMgCl. LiCl (9 mL, 11.61 mmol, 1.3M THF solution). The resulting mixture was stirred at-10 ℃ for 30 minutes under nitrogen atmosphere. To the above mixture was added dropwise at-10 ℃ over 5 minutes (3)S) -3- [ methoxy (methyl) carbamoyl ]Pyrrolidine-1-carboxylic acid tert-butyl ester (0.50 g, 1.94 mmol) in THF (1 mL). The resulting mixture was stirred at-10 ℃ for an additional 2 hours. The reaction was quenched with saturated NH at room temperature₄Aqueous Cl (20 mL) was quenched. The resulting mixture was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (4/1) to give (3) as a pale yellow oilS) -3- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (0.25 g, 32%): C₁₉H₂₃Cl₂NO₄ [M + Na]⁺Calculated lcms (esi): 422, 424 (3: 2), found 422, 424 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.79 (s, 1H), 7.08 (s, 1H), 6.13-6.00 (m, 1H), 5.55-5.24 (m, 2H), 4.69-4.56 (m, 2H), 4.03-3.90 (m, 1H), 3.71-3.54 (m, 2H), 3.54-3.32 (m, 2H), 2.26-2.01 (m, 2H), 1.48 (s, 9H)。

step b:

stirring at room temperature (3)S) -3- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl]T was added to a solution of pyrrolidine-1-carboxylic acid tert-butyl ester (0.25 g, 0.63 mmol) and tert-butanesulfinamide (0.23 g, 1.87 mmol) in THF (5 mL)i(OEt)₄(0.85 g, 3.75 mmol). The resulting solution was stirred at 70 ℃ for 16 hours under nitrogen atmosphere. The reaction was quenched with saturated NaHCO at room temperature₃Aqueous solution (20 mL) was quenched. The resulting mixture was filtered and the filter cake was washed with EA (3X 10 mL). The resulting mixture was extracted with EA (3X 20 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (1/1) to give (3) as a pale yellow oilS) -3- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][ (2-methylpropane-2-sulfinyl) imino]Methyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (0.30 g, 76%): C₂₃H₃₂Cl₂N₂O₄S [M + Na]⁺Calculated lcms (esi): 525, 527 (3: 2), found 525, 527 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.18 (s, 1H), 6.98 (s, 1H), 6.06-5.91 (m, 1H), 5.45-5.28 (m, 2H), 4.63-4.52 (m, 2H), 3.77-3.64 (m, 3H), 3.59-3.46 (m, 1H), 3.40-3.29 (m, 1H), 2.29-1.92 (m, 2H), 1.50-1.45 (m, 9H), 1.24 (s, 9H)。

step c:

stirring at room temperature (3)S) -3- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][ (2-methylpropane-2-sulfinyl) imino]Methyl radical]To a solution of pyrrolidine-1-carboxylic acid tert-butyl ester (0.30 g, 0.60 mmol) in THF (5 mL) was added NaBH₄(68 mg, 1.79 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (20 mL) and extracted with EA (3X 20 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give (3) as a pale yellow oilS) -3- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (0.30 g, crude), which was used in the next step without further purification: c ₂₃H₃₄Cl₂N₂O₄S [M + H]⁺Lcms (esi) calculated value of (a): 505, 507 (3: 2), found 505, 507 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.31 (s, 1H), 6.97 (s, 1H), 6.10-5.96 (m, 1H), 5.40 (dd, J = 26.3, 13.9 Hz, 2H), 4.65-4.51 (m, 2H), 3.77-3.65 (m, 3H), 3.55-3.42 (m, 1H), 3.37-3.15 (m, 2H), 3.04-2.58 (m, 1H), 1.88-1.71 (m, 1H), 1.51-1.44 (m, 9H), 1.17 (d, J = 8.2 Hz, 9H)。

step d:

stirring at room temperature (3)S) -3- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] carbonyl][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]To a solution of pyrrolidine-1-carboxylic acid tert-butyl ester (0.30 g, 0.60 mmol) in DCM (2 mL) was added TFA (0.4 mL). The resulting mixture was stirred at room temperature for 30 minutes. The reaction was quenched with saturated NaHCO at room temperature₃The aqueous solution (20 mL) was neutralized to pH 7 and extracted with EA (3X 20 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to obtain as a pale yellow solidN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]((3S) -pyrrolidin-3-yl) methyl]2-methylpropane-2-sulfinamide (0.30 g, crude), which was used in the next step without further purification: c₁₈H₂₆Cl₂N₂O₂S [M + H]⁺Calculated lcms (esi): 405, 407 (3: 2), found 405, 407 (3: 2).

Step e:

stirring at room temperature (4)R) To a mixture of-2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid (0.32 g, 2.22 mmol) and HATU (1.13 g, 2.96 mmol) in DMF (5 mL) was addedN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ]((3S) -pyrrolidin-3-yl) methyl]2-methylpropane-2-sulfinamide (0.30 g, 0.74 mmol) and Et₃N (0.22 g, 2.22 mmol). The resulting mixture was stirred at room temperature for 1 hour. The residue was purified by reverse phase chromatography eluting with 57% aqueous ACN (plus 0.05% TFA) to afford the product as an off-white solidN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][(3S)-1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Pyrrolidin-3-yl radical]Methyl radical]2-methylpropane-2-sulfinamide (0.20 g, 60% of the total of the three steps): C₂₄H₃₄Cl₂N₂O₅S [M + H]⁺Calculated lcms (esi): 533, 535 (3: 2), found 533, 535 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.28-7.23 (m, 1H), 7.02-6.96 (m, 1H), 6.13-5.98 (m, 1H), 5.51-5.33 (m, 2H), 4.83-4.43 (m, 4H), 4.40-4.26 (m, 1H), 4.26-4.09 (m, 1H), 3.92-3.57 (m, 2H), 3.48-3.24 (m, 1H), 3.10-2.56 (m, 2H), 2.48-2.13 (m, 1H), 1.95-1.67 (m, 1H), 1.47-1.39 (m, 6H), 1.17-1.14 (m, 9H)。

step f:

at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][(3S)-1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Pyrrolidin-3-yl radical]Methyl radical]-2-methylpropane-2-sulfinamide (0.20 g, 0.38 mmol) and Pd (PPh)₃)₄(4 mg, 0.004 mmol) in THF (3 mL) NaBH was added₄(28 mg, 0.75 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The resulting mixture was washed with saturated NH₄Aqueous Cl (1 mL) was quenched and concentrated under reduced pressure to give a brown solidN- [ (4, 5-dichloro-2-hydroxyphenyl) [ (3)S)-1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl ]Pyrrolidin-3-yl]Methyl radical]2-methylpropane-2-sulfinamide (0.20 g, crude), which was used in the next step without further purification: c₂₁H₃₀Cl₂N₂O₅S [M + H]⁺Lcms (esi) calculated value of (a): 493, 495 (3: 2), found 493, 495 (3: 2).

Step g:

at room temperature with stirringN- [ (4, 5-dichloro-2-hydroxyphenyl) [ (3)S)-1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Pyrrolidin-3-yl radical]Methyl radical]To a mixture of (E) -2-methylpropane-2-sulfinamide (0.20 g, 0.41 mmol) in 1, 4-dioxane (1 mL) was added aqueous HCl (4)N1 mL). The resulting mixture was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xselect CSH OBD column 30 × 150 mm 5 μm, n; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 9 minutesFrom 5% B to 20% B; a detector: UV 254/220 nm; retention time: RT (reverse transcription)₁6.05 min, RT₂8.92 minutes.

The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 308 ((2) as an off-white solidR)-1-[(3S) -3- [ amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Pyrrolidin-1-yl radical]-2, 3-dihydroxypropan-1-one isomer 1) (17.5 mg, 13% of two steps in total): C ₁₄H₁₈Cl₂N₂O₄ [M + H]⁺Lcms (esi) calculated value of (a): 349, 351 (3: 2), found 349, 351 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.32 (d, J = 5.5 Hz, 1H), 6.90 (s, 1H), 4.28 (dt, J = 48.6, 5.8 Hz, 1H), 4.08-3.78 (m, 2H), 3.78-3.53 (m, 3H), 3.50-3.35 (m, 1H), 3.28-3.00 (m, 1H), 2.82-2.58 (m, 1H), 2.38-2.17 (m, 1H), 1.97-1.67 (m, 1H)。

the fractions containing the desired product were collected at 8.92 minutes and concentrated under reduced pressure to afford compound 312 ((2) as an off-white solidR)-1-[(3S) -3- [ amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Pyrrolidin-1-yl radical]-2, 3-dihydroxypropan-1-one isomer 2) (34.1 mg, 26% of two steps in total): C₁₄H₁₈Cl₂N₂O₄ [M + H]⁺Calculated lcms (esi): 349, 351 (3: 2), found 349, 351 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.32 (d, J = 11.6 Hz, 1H), 6.91 (d, J = 7.4 Hz, 1H), 4.39 (dt, J = 29.3, 5.8 Hz, 1H), 4.06-3.90 (m, 2H), 3.91-3.60 (m, 3H), 3.61-3.41 (m, 1H), 3.30-3.23 (m, 1H), 2.81-2.58 (m, 1H), 1.81-1.50 (m, 2H)。

example 240 Compound 309 (, (2R) -1- [4- [ amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]-4-methylpiperidin-1-yl]-2, 3-dihydroxypropan-1-one trifluoroacetic acid)

Step a:

stirring at-60 deg.C under nitrogen atmosphere4- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl]To a solution of tert-butyl piperidine-1-carboxylate (0.50 g, 1.21 mmol) in THF (5 mL) was added LiHMDS (2.41 mL, 2.41 mmol, 1M in THF). The reaction was stirred at-60 ℃ for 0.5 h. MeI (0.51 g, 3.62 mmol) was then added to the reaction. The reaction was stirred at-60 ℃ to room temperature for 2 hours. Reacting with saturated NH₄Aqueous Cl (2 mL) was quenched and diluted with EA (20 mL) and water (30 mL). The aqueous layer was extracted with EA (3X 20 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with PE/EA (10/1) to give 4- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl group as a pale yellow oil]4-methylpiperidine-1-carboxylic acid tert-butyl ester (0.28 g, 54%): C₂₁H₂₇Cl₂NO₄ [M + Na]⁺Calculated lcms (esi): 450, 452 (3: 2), found 428, 430 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.14 (s, 1H), 7.02 (s, 1H), 6.07-5.91 (m, 1H), 5.43-5.30 (m, 2H), 4.54 (d, J = 5.7 Hz, 2H), 3.62-3.42 (m, 2H), 3.42-3.31 (m, 2H), 2.05-1.95 (m, 2H), 1.62-1.54 (m, 2H), 1.54 (s, 9H), 1.30 (s, 3H)。

step b:

to a stirred 4- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl group at room temperature under nitrogen atmosphere](iii) -4-methylpiperidine-1-carboxylic acid tert-butyl ester (0.28 g, 0.65 mmol) and tert-butanesulfinamide (0.24 g, 1.96 mmol) in THF (5 mL) Ti (OEt) was added₄(1.49 g, 6.54 mmol). The reaction was stirred at 70 ℃ for 16 hours. The reaction was saturated with Na₂CO₃Aqueous solution (30 mL) was quenched. The resulting mixture was filtered through celite (celite), and the filtrate was diluted with water (30 mL). The aqueous layer was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] in the form of a pale yellow oil][ (2-methylpropane-2-sulfinyl) imino]Methyl radical]-4-methylpiperidine-1-carboxylic acid tert-butyl ester (0.44 g, crude), which is not further processed Step (ii) purification was used directly in the next step: c₂₅H₃₆Cl₂N₂O₄S[M + H]⁺Lcms (esi) calculated value of (a): 531, 533 (3: 2), found 531, 533 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.27-7.20 (m, 2H), 6.11-5.97 (m, 1H), 5.49-5.39 (m, 1H), 5.35-5.28 (m, 1H), 4.65-4.57 (m, 2H), 3.88-3.56 (m, 2H), 3.38-3.33 (m, 1H), 3.31-3.21 (m, 1H), 2.02-1.84 (m, 2H), 1.78-1.58 (m, 2H), 1.46 (d, J = 1.8 Hz, 9H), 1.29 (s, 3H), 1.23 (s, 9H)。

step c:

to a stirred 4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl group at room temperature][ (2-methylpropane-2-sulfinyl) imino]Methyl radical](ii) -4-methylpiperidine-1-carboxylic acid tert-butyl ester (0.44 g, 0.83 mmol) in THF (5 mL) and MeOH (2 mL) NaBH was added portionwise₄(0.13 g, 3.31 mmol). The reaction was stirred at room temperature for 8 hours. Reacting with saturated NH₄Aqueous Cl (2 mL) was quenched and diluted with water (30 mL). The aqueous layer was extracted with EA (3X 20 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] as a pale yellow solid][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]4-methylpiperidine-1-carboxylic acid tert-butyl ester (0.33 g, 75%): C₂₅H₃₈Cl₂N₂O₄S[M + H]⁺Calculated lcms (esi): 533, 535 (3: 2), found 533, 535 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.52 (s, 1H), 7.18 (s, 1H), 6.16-6.05 (m, 1H), 5.46 (d, J = 17.1 Hz, 1H), 5.34 (d, J = 10.7 Hz, 1H), 4.70-4.56 (m, 2H), 3.92-3.75 (m, 3H), 3.13-2.93 (m, 4H), 1.66-1.60 (m, 2H), 1.46 (s, 9H), 1.23 (s, 3H), 1.14 (s, 9H)。

step d:

to a stirred 4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl group at room temperature][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]To a solution of tert-butyl-4-methylpiperidine-1-carboxylate (0.33 g, 0.62 mmol) in DCM (5 mL) was added TFA (1 mL). The reaction was stirred at room temperature Stirring for 0.5 hour. The reaction was quenched with saturated Na at 0 deg.C₂CO₃The aqueous solution (20 mL) was neutralized to pH 7. The resulting solution was diluted with water (30 mL). The aqueous layer was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. Filtering, concentrating the filtrate under reduced pressure to obtain yellow oilN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](4-methylpiperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (400 mg, crude), which was used in the next step without further purification: c₂₀H₃₀Cl₂N₂O₂S[M + H]⁺Calculated lcms (esi): 433, 435 (3: 2), found 433, 435 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.56 (s, 1H), 7.22 (s, 1H), 6.18-6.04 (m, 1H), 5.51-5.30 (m, 2H), 4.68-4.57 (m, 3H), 3.31-3.23 (m, 2H), 3.22-3.02 (m, 2H), 1.94-1.69 (m, 4H), 1.23 (s, 3H), 1.14 (s, 9H)。

step e:

stirring at room temperature (4R) To a solution of (E) -2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid (0.20 g, 1.38 mmol) and HATU (0.53 g, 1.38 mmol) in DMF (3 mL) was addedN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](4-methylpiperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide (0.40 g, 0.92 mmol) and Et₃N (0.28g, 2.77 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was purified by reverse phase chromatography eluting with 50% aqueous ACN (plus 0.05% TFA) to afford as a colorless oilN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]-4-methylpiperidin-4-yl]) Methyl radical]2-methylpropane-2-sulfinamide (0.13 g, 37% in two steps) C₂₆H₃₈Cl₂N₂O₅S [M + H]⁺Lcms (esi) calculated value of (a): 561, 563 (3: 2), found 561, 563 (3: 2); ¹H NMR (400 MHz, CD₃OD) δ 7.52 (s, 1H), 7.18 (s, 1H), 6.20-6.02 (m, 1H), 5.52-5.38 (m, 1H), 5.38-5.28 (m, 1H), 4.71-4.58 (m, 2H), 4.35-4.16 (m, 4H), 4.04-3.82 (m, 1H), 3.77-3.54 (m, 1H), 3.24-2.85 (m, 2H), 1.88-1.51 (m, 4H), 1.42-1.34 (m, 6H), 1.27 (d, J = 7.1 Hz, 3H), 1.16 (d, J = 14.9 Hz, 9H)。

step f:

at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]-4-methylpiperidin-4-yl]) Methyl radical]-2-methylpropane-2-sulfinamide (0.13 g, 0.23 mmol) and Pd (PPh)₃)₄ (5 mg, 0.01 mmol) in THF (2 mL) NaBH was added₄ (18 mg, 0.46 mmol). The reaction was stirred at room temperature for 0.5 h. Concentrating the reaction under reduced pressure to obtain the product as brown solidN- [ (4, 5-dichloro-2-hydroxyphenyl) ([1- [ (S))4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]-4-methylpiperidin-4-yl]) Methyl radical]2-methylpropane-2-sulfinamide (0.12 g, crude), which was used in the next step without further purification: c₂₃H₃₄Cl₂N₂O₅S [M + H]⁺Calculated lcms (esi): 521, 523 (3: 2), found 521, 523 (3: 2).

Step g:

at room temperature with stirringN- [ (4, 5-dichloro-2-hydroxyphenyl) ([1- [ (S))4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]-4-methylpiperidin-4-yl ]) Methyl radical]-2-methylpropane-2-sulfinamide (0.12 g, 0.23 mmol) in THF (2 mL) aqueous HCl (4) was addedN1 mL). The reaction was stirred at room temperature for 1 hour. The reaction was performed with EA (20 mL) and HCl (1)N20 mL). The organic layer was washed with aqueous HCl (1)N2X 20 mL). The combined aqueous layers were concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xselect CSH OBD column 30 × 150 mm 5 μm n; mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 10% B to 25% B in 7 minutes; a detector: UV 254/220 nm; retention time: 5.58 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 309 (, (r) as an off-white solid2R) -1- [4- [ amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]-4-methylpiperidin-1-yl]-2, 3-dihydroxypropan-1-one trifluoroacetic acid) (63 mg, 56% in two steps total) C₁₆H₂₂Cl₂N₂O₄ [M + H]⁺Calculated lcms (esi): 377, 379 (3: 2), found 377, 379 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.42 (s, 1H), 7.09 (s, 1H), 4.63-4.26 (m, 3H), 4.09-3.93 (m, 1H), 3.78-3.60 (m, 2H), 3.30-3.20 (m, 1H), 3.12-2.85 (m, 1H), 1.78-1.54 (m, 3H), 1.41-1.28 (m, 1H), 1.21 (s, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.15.

example 241 Compound 310 ((2)R)-1-[(3R)-3-[(S) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Pyrrolidin-1-yl radical]-2, 3-dihydroxypropan-1-one); compound 311 ((2)R)-1-[(3R)-3-[(R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group ]Pyrrolidin-1-yl]-2, 3-dihydroxypropan-1-one)

A, step a:

to a stirred mixture of 1-bromo-4, 5-dichloro-2- (prop-2-en-1-yloxy) benzene (example 6, step b) (5.46 g, 19.36 mmol) in THF (30 mL) at-10 deg.C under a nitrogen atmosphere was added dropwisei-PrMgCl. LiCl (18 mL, 23.23 mmol, 1.3M THF solution). The resulting mixture was stirred at-10 ℃ for 30 minutes under nitrogen atmosphere. To the above mixture was added dropwise at-10 ℃ over 5 minutes (3)R) -3- [ methoxy (methyl) carbamoyl]A solution of pyrrolidine-1-carboxylic acid tert-butyl ester (1.00 g, 3.87 mmol) in THF (1 mL). The resulting mixture was stirred at-10 ℃ for an additional 2 hours. The reaction was quenched with saturated NH at room temperature₄Aqueous Cl (20 mL) was quenched. The resulting mixture was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (4/1) to give (3) as a pale yellow oilR) -3- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl]Pyrrolidine-1-carboxylic acid tert-butyl ester (0.45 g, 23%): C₁₉H₂₃Cl₂NO₄[M + Na]⁺L ofCms (esi) calculated value: 422, 424 (3: 2), found 422, 424 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.79 (s, 1H), 7.08 (s, 1H), 6.14-5.95 (m, 1H), 5.53-5.33 (m, 2H), 4.64 (d, J = 5.7 Hz, 2H), 4.03-3.91 (m, 1H), 3.68-3.54 (m, 2H), 3.51-3.35 (m, 2H), 2.21-2.04 (m, 2H), 1.48 (s, 9H)。

step b:

Stirring at room temperature (3)R) -3- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl]To a solution of pyrrolidine-1-carboxylic acid tert-butyl ester (0.25 g, 0.63 mmol) and tert-butanesulfinamide (0.23 g, 1.87 mmol) in THF (5 mL) was added Ti (OEt)₄(0.85 g, 3.75 mmol). The resulting solution was stirred at 70 ℃ for 16 hours under nitrogen atmosphere. The reaction was quenched with saturated NaHCO at room temperature₃Aqueous solution (20 mL) was quenched. The resulting mixture was filtered and the filter cake was washed with EA (3X 10 mL). The resulting mixture was extracted with EA (3X 20 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (1/1) to give (3) as a pale yellow oilR) -3- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][ (2-methylpropane-2-sulfinyl) imino]Methyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (0.30 g, 67%): C₂₃H₃₂Cl₂N₂O₄S [M + Na]⁺Calculated lcms (esi): 525, 527 (3: 2), found 525, 527 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.18 (s, 1H), 6.99 (s, 1H), 6.08-5.94 (m, 1H), 5.48-5.28 (m, 2H), 4.62-4.52 (m, 2H), 3.76-3.61 (m, 3H), 3.60-3.46 (m, 1H), 3.41-3.29 (m, 1H), 2.34-1.94 (m, 2H), 1.47 (s, 9H), 1.24 (s, 9H)。

step c:

stirring at room temperature (3)R) -3- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][ (2-methylpropane-2-sulfinyl) imino]Methyl radical]To a solution of pyrrolidine-1-carboxylic acid tert-butyl ester (0.30 g, 0.60 mmol) in THF (5 mL) was added NaBH ₄(68 mg, 1.79 mmol). The resulting mixture was stirred at room temperature for 1 hour. Quench the reaction with water (20 mL) and useEA (3X 20 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give (3) as a pale yellow oilR) -3- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]Pyrrolidine-1-carboxylic acid tert-butyl ester (0.30 g, crude), which was used in the next step without further purification: c₂₃H₃₄Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 505, 507 (3: 2), found 505, 507 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.33 (s, 1H), 6.97 (s, 1H), 6.10-5.95 (m, 1H), 5.48-5.30 (m, 2H), 4.66-4.48 (m, 2H), 3.77-3.41 (m, 4H), 3.38-3.13 (m, 2H), 2.73-2.58 (m, 1H), 1.90-1.65 (m, 1H), 1.50-1.43 (m, 9H), 1.25 (s, 9H)。

step d:

stirring at room temperature (3)R) -3- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]To a solution of pyrrolidine-1-carboxylic acid tert-butyl ester (0.30 g, 0.60 mmol) in DCM (2 mL) was added TFA (0.4 mL). The resulting mixture was stirred at room temperature for 30 minutes. The reaction was quenched with saturated NaHCO at room temperature₃The aqueous solution (20 mL) was neutralized to pH 7 and extracted with EA (3X 20 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to obtain as a pale yellow solid N- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]((3R) -pyrrolidin-3-yl) methyl]2-methylpropane-2-sulfinamide (0.30 g, crude), which was used in the next step without further purification: c₁₈H₂₆Cl₂N₂O₂S [M + H]⁺Lcms (esi) calculated value of (a): 405, 407 (3: 2), found 405, 407 (3: 2).

Step e:

stirring at room temperature (4)R) To a mixture of-2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid (0.32 g, 2.22 mmol) and HATU (1.13 g, 2.96 mmol) in DMF (5 mL) was addedN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]((3R) -pyrrolidin-3-yl) methyl]2-methylpropane-2-sulfinamide (0.30 g, 0.74 mmol) and Et₃N (0.22 g, 2.22 mmol). The resulting mixture was stirred at room temperature for 1 hour. The residue was purified by reverse phase chromatography eluting with 57% aqueous ACN (plus 0.05% TFA) to afford the product as an off-white solidN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][(3R)-1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Pyrrolidin-3-yl radical]Methyl radical]2-methylpropane-2-sulfinamide (0.20 g, 60% of the total of the four stages): C₂₄H₃₄Cl₂N₂O₅S [M + H]⁺Calculated lcms (esi): 533, 535 (3: 2), found 533, 535 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.27-7.21 (m, 1H), 7.03-6.95 (m, 1H), 6.14-5.97 (m, 1H), 5.50-5.31 (m, 2H), 4.81-4.67 (m, 1H), 4.67-4.50 (m, 3H), 4.45-4.20 (m, 1H), 4.20-4.09 (m, 1H), 4.05-3.74 (m, 1H), 3.71-3.55 (m, 1H), 3.52-3.28 (m, 1H), 2.86-2.58 (m, 1H), 2.27-1.96 (m, 2H), 1.92-1.59 (m, 1H), 1.53-1.28 (m, 6H), 1.20-1.12 (m, 9H)。

step f:

at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ][(3R)-1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Pyrrolidin-3-yl]Methyl radical]-2-methylpropane-2-sulfinamide (0.20 g, 0.38 mmol) and Pd (PPh)₃)₄(4 mg, 0.004 mmol) in THF (3 mL) NaBH was added₄(43 mg, 1.13 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The resulting mixture was washed with saturated NH₄Aqueous Cl (1 mL) was quenched and concentrated under reduced pressure to give a brown solidN- [ (4, 5-dichloro-2-hydroxyphenyl) [ (3)R)-1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Pyrrolidin-3-yl radical]Methyl radical]2-methylpropane-2-sulfinamide (0.20 g, crude), which was used in the next step without further purification: c₂₁H₃₀Cl₂N₂O₅S [M + H]⁺Calculated lcms (esi): 493, 495 (3: 2), found 493, 495 (3: 2).

Step g:

at room temperature with stirringN- [ (4, 5-dichloro-2-hydroxyphenyl) [ (3)R)-1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Pyrrolidin-3-yl radical]Methyl radical]To a mixture of (E) -2-methylpropane-2-sulfinamide (0.20 g, 0.41 mmol) in 1, 4-dioxane (1 mL) was added aqueous HCl (4)N1 mL). The resulting mixture was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Shield RP18 OBD column, 30X 150 mm, 5 μm; mobile phase A: having a NH concentration of 10 mmol/L ₄HCO₃Water, mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 15% B to 40% B in 7 minutes; a detector: UV 254/220 nm; retention time: RT (reverse transcription)₁6.50 minutes; RT (reverse transcription)₂6.70 minutes.

Fractions containing the desired product were collected at 6.50 minutes and concentrated under reduced pressure to afford compound 310 ((2) as an off-white solidR)-1-[(3R)-3-[(S) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Pyrrolidin-1-yl radical]-2, 3-dihydroxypropan-1-one) (15.6 mg, 11% of two steps in total): C₁₄H₁₈Cl₂N₂O₄ [M + H]⁺Calculated lcms (esi): 349, 351 (3: 2), found 349, 351 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.32 (d, J =4.9 Hz, 1H), 6.90 (s, 1H), 4.30 (dt, J = 51.2, 5.4 Hz, 1H), 4.07-3.84 (m, 2H), 3.78-3.41 (m, 4H), 3.31-3.01 (m, 1H), 2.82-2.63 (m, 1H), 2.38-2.15 (m, 1H), 1.97-1.66 (m, 1H)。

the fractions containing the desired product were collected at 6.70 minutes and concentrated under reduced pressure to give compound 311 ((2) as an off-white solidR)-1-[(3R)-3-[(R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Pyrrolidin-1-yl radical]-2, 3-dihydroxypropan-1-one) (31.3 mg, 22% of two steps in total): C₁₄H₁₈Cl₂N₂O₄ [M + H]⁺Calculated lcms (esi): 349, 351 (3: 2), found 349, 351 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.32 (d, J =9.7 Hz, 1H), 6.90 (d, J = 7.4 Hz, 1H), 4.40 (dt, J = 24.9, 5.5 Hz, 1H), 4.08-3.89 (m, 2H), 3.85-3.36 (m, 4H), 3.30-3.22 (m, 1H), 2.81-2.58 (m, 1H), 1.80-1.52 (m, 2H)。

example 242 Compound 313 ((2R) -1- [8- [ (R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl ] -3-azabicyclo [3.2.1] octan-3-yl ] -2, 3-dihydroxypropan-1-one trifluoroacetic acid); compound 314 ((2R) -1- [8- [ (S) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl ] -3-azabicyclo [3.2.1] octan-3-yl ] -2, 3-dihydroxypropan-1-one trifluoroacetic acid)

Step a:

to a stirred solution of 1-bromo-4, 5-dichloro-2- (prop-2-en-1-yloxy) benzene (0.61 g, 2.16 mmol) in THF (5 mL) at 0 deg.C under a nitrogen atmosphere was added dropwisei-PrMgCl (1.44 mL, 2.88 mmol, 2M in THF). After stirring at 0 ℃ for 30 minutes under a nitrogen atmosphere, 8- [ methoxy (methyl) carbamoyl group]-3-azabicyclo [ 2 ]3.2.1]A solution of tert-butyl octane-3-carboxylate (intermediate 22, example 22) (0.43 g, 1.44 mmol) in THF (2 mL) was added dropwise to the resulting solution. The reaction was stirred at 0 ℃ for an additional 1 hour. Reacting with saturated NH₄Aqueous Cl (2 mL) was quenched at 0 ℃ and diluted with EA (20 mL) and water (30 mL). The aqueous layer was extracted with EA (3X 20 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with PE/EA (6/1) to give 8- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl group as a colorless oil]-3-azabicyclo [ 2 ]3.2.1]Octane-3-carboxylic acid tert-butyl ester (0.30 g, 45%): C₂₂H₂₇Cl₂NO₄ [M + Na]⁺Calculated lcms (esi): 462, 464 (3: 2), found 462, 464 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.68 (d, J = 9.9 Hz, 1H), 7.07 (d, J = 6.3 Hz, 1H), 6.14-5.96 (m, 1H), 5.44 (dt, J = 25.1, 8.5 Hz, 2H), 4.63 (dd, J = 18.1, 5.5 Hz, 2H), 4.07-3.79 (m, 1H), 3.79-3.48 (m, 1H), 3.27-2.84 (m, 2H), 2.58-2.37 (m, 2H), 1.86-1.72 (m, 1H), 1.72-1.50 (m, 4H), 1.47 (d, J = 9.5 Hz, 9H)。

step b:

to a stirred 8- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl group at room temperature under nitrogen atmosphere ]-3-azabicyclo [ 2 ]3.2.1]To a solution of tert-butyl octane-3-carboxylate (0.30 g, 0.65 mmol) and tert-butanesulfinamide (0.24 g, 1.95 mmol) in THF (5 mL) was added Ti (OEt)₄(1.48 g, 6.50 mmol). The reaction was warmed to 70 ℃ and stirred under nitrogen for 16 hours. The reaction was saturated with Na₂CO₃Aqueous solution (30 mL) was quenched. The resulting mixture was filtered through celite (celite), and the filtrate was diluted with EA (30 mL) and water (30 mL). The aqueous layer was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 8- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] in the form of a yellow oil][ (2-methylpropane-2-sulfinyl) imino]Methyl radical]-3-azabicyclo [ 2 ]3.2.1]Octane-3-carboxylic acid tert-butyl ester (0.43 g, crude), which was used in the next step without further purification: c₂₆H₃₆Cl₂N₂O₄S[M + H]⁺Calculated lcms (esi): 543, 545 (3: 2), measured values 543, 545 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.29 (s, 1H), 6.98 (s, 1H), 6.09-5.90 (m, 1H), 5.36 (dd, J = 35.9, 13.9 Hz, 2H), 4.73-4.49 (m, 2H), 4.04-3.54 (m, 5H), 2.99-2.65 (m, 2H), 2.60-2.13 (m, 1H), 2.00-1.57 (m, 3H), 1.47 (d, J = 3.8 Hz, 9H), 1.24 (s, 9H)。

step c:

to a stirred 8- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl group at room temperature][ (2-methylpropane-2-sulfinyl) imino]Methyl radical]-3-azabicyclo [ 2 ]3.2.1]To a solution of tert-butyl octane-3-carboxylate (0.43 g, 0.79 mmol) in THF (5 mL) and MeOH (3 mL) was added NaBH ₄(0.24 g, 6.33 mmol). The reaction was stirred at room temperature for 8 hours. Reacting with saturated NH₄Aqueous Cl (2 mL) was quenched and then diluted with water (30 mL). The aqueous layer was extracted with EA (3X 20 mL). Will be combinedThe combined organic layers were washed with brine (2X 20 mL) and over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 8- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] as a pale yellow solid][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]-3-azabicyclo [ 2 ]3.2.1]Octane-3-carboxylic acid tert-butyl ester (0.34 g, 96% of two steps in total): C₂₆H₃₈Cl₂N₂O₄S[M + H]⁺Calculated lcms (esi): 545, 547 (3: 2), found 545, 547 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.58-7.44 (m, 1H), 7.17 (s, 1H), 6.15-5.98 (m, 1H), 5.57-5.26 (m, 2H), 4.70-4.49 (m, 2H), 3.99-3.88 (m, 1H), 3.80-3.66 (m, 1H), 3.54-3.35 (m, 1H), 3.03-2.82 (m, 1H), 2.82-2.42 (m, 2H), 2.02-1.68 (m, 3H), 1.66-1.51 (m, 3H), 1.46 (s, 9H), 1.23 (s, 9H)。

step d:

to a stirred 8- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl group at room temperature][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]-3-azabicyclo [ 2 ]3.2.1]To a solution of tert-butyl octane-3-carboxylate (0.34 g, 0.62 mmol) in DCM (5 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 0.5 h, saturated Na was used for the reaction₂CO₃Aqueous solution (20 mL) was quenched with saturated Na₂CO₃The aqueous solution (30 mL) was neutralized to pH 7. The resulting solution was diluted with EA (30 mL) and water (30 mL), and the aqueous layer was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give an off-white solidN- [ 3-azabicyclo [ 2 ]3.2.1]Octane-8-yl [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]2-methylpropane-2-sulfinamide (0.30 g, crude), which was used in the next step without further purification: c₂₁H₃₀Cl₂N₂O₂S [M + H]⁺Lcms (esi) calculated value of (a): 445, 447, (3: 2), found 445, 447, (3: 2).

Step e:

stirring at room temperature (4R) -2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid (0.15 g, 1.01 mmol) and HATU (0.38 g, 1.01 mmol) in DMF (5 mL) were addedN[ 3-azabicyclo [ 2 ]3.2.1]Octane-8-yl [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]-2-methylpropane-2-sulfinamide (0.30 g, 0.67 mmol) and Et₃N (0.20 g, 2.02 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was purified by reverse phase chromatography, diluted with 56% aqueous ACN (plus 0.05% TFA) to give as a colorless oilN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([3-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]-3-azabicyclo [ 2 ]3.2.1]Octane-8-yl]) Methyl radical]2-methylpropane-2-sulfinamide (0.20 g, 56% of two-step total): C₂₇H₃₈Cl₂N₂O₅S [M + H]⁺Calculated lcms (esi): 573, 575 (3: 2), found 573, 575 (3: 2). ¹H NMR (400 MHz, CD₃OD) δ 7.65-7.47 (m, 1H), 7.22-7.16 (m, 1H), 6.25-6.00 (m, 1H), 5.40 (dd, J = 43.9, 14.0 Hz, 2H), 4.76-4.41 (m, 2H), 4.44-4.17 (m, 2H), 4.17-4.07 (m, 1H), 4.02-3.88 (m, 1H), 3.86-3.50 (m, 2H), 3.21-2.77 (m, 1H), 2.75-2.64 (m, 1H), 2.64-2.53 (m, 1H), 2.32-2.09 (m, 1H), 2.01-1.82 (m, 2H), 1.73-1.59 (m, 3H) 1.45-1.30 (m, 6H), 1.12 (s, 9H)。

Step f:

at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([3-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]-3-azabicyclo [ 2 ]3.2.1]Octane-8-yl]) Methyl radical]-2-methylpropane-2-sulfinamide (0.20 g, 0.35 mmol) and Pd (PPh)₃)₄(40 mg, 0.04 mmol) in THF (5 mL) NaBH was added₄ (26 mg, 0.70 mmol). The reaction was stirred at room temperature for 30 minutes. Reacting with saturated NH₄Aqueous Cl (1 mL) was quenched and concentrated under reduced pressure to give a yellow oilN- [ (4, 5-dichloro-2-hydroxyphenyl) ([3- [ (S))4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]-3-azabicyclo [ 2 ]3.2.1]Octane-8-yl]) Methyl radical]2-methylpropane-2-sulfinamide (0.20 g, crude), which was used in the next step without further purification: c₂₄H₃₄Cl₂N₂O₅S [M + H]⁺Calculated lcms (esi): 533, 535 (3: 2), found 533, 535 (3: 2).

Step g:

at room temperature with stirringN- [ (4, 5-dichloro-2-hydroxyphenyl) ([3- [ (S))4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]-3-azabicyclo [ 2 ]3.2.1]Octane-8-yl]) Methyl radical](iii) -2-methylpropane-2-sulfinamide (0.20 g, 0.38 mmol) in 1, 4-dioxane (5 mL) to which was added aqueous HCl (4)N2 mL). The reaction was stirred at room temperature for 1 hour. The reaction was performed with EA (20 mL) and HCl (1) N20 mL). The organic layer was washed with aqueous HCl (1)N2X 20 mL). The combined aqueous layers were concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xselect CSH OBD column 30X 150 mm 5 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 5% B to 25% B in 8 minutes; a detector: UV 254/220 nm; retention time: RT (reverse transcription)₁8.65 min, RT₂9.32 minutes.

The fractions containing the desired product were collected at 8.65 minutes and concentrated under reduced pressure to give compound 313 (, (R) as an off-white solid2R)-1-[8-[(R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]-3-azabicyclo [ 2 ]3.2.1]Octane-3-yl]-2, 3-dihydroxypropan-1-one trifluoroacetic acid) (57.7 mg, 33% of two steps in total) C₁₇H₂₂Cl₂N₂O₄ [M + H]⁺Calculated lcms (esi): 389, 391 (3: 2), found 389, 391 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.48 (d, J = 2.8 Hz, 1H), 7.11 (s, 1H), 4.58-4.24 (m, 1H), 4.24-4.01 (m, 2H), 3.93-3.55 (m, 3H), 3.30-3.05 (m, 1H), 2.78-2.72 (m, 1H), 2.63-2.39 (m, 2H), 2.03-1.93 (m, 1H), 1.93-1.82 (m, 1H), 1.80-1.43 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.19.

the fractions containing the desired product were collected at 9.32 minutes and concentrated under reduced pressure to give compound 314 (a) (b)2R)-1-[8-[(S) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]-3-azabicyclo [ 2 ]3.2.1]Octane-3-yl]-2, 3-dihydroxypropan-1-one trifluoroacetic acid) (13.3 mg, 10% of two steps in total) C₁₇H₂₂Cl₂N₂O₄ [M + H]⁺Calculated lcms (esi): 389, 391 (3: 2), found 389, 391 (3: 2); ¹H NMR (400 MHz, CD₃OD) δ 7.59 (d, J = 6.3 Hz, 1H), 7.12 (s, 1H), 5.02 (s, 1H), 4.64-4.44 (m, 1H), 4.27-3.95 (m, 1H), 3.95-3.59 (m, 3H), 3.54-3.48 (m, 1H), 3.26-3.01 (m, 1H), 2.62-2.49 (m, 1H), 2.49-2.36 (m, 1H), 1.99-1.83 (m, 1H), 1.83-1.75 (m, 2H), 1.75-1.47 (m, 2H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -76.98.

Example 243 Compound 315 ((2)R)-1-(5-((R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) -2-azabicyclo [2.2.1]Heptane-2-yl) -2, 3-dihydroxypropan-1-one trifluoroacetic acid); compound 316 ((2)R)-1-(5-((S) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) -2-azabicyclo [2.2.1]Heptane-2-yl) -2, 3-dihydroxypropan-1-one trifluoroacetic acid

Step a:

to a stirred solution of 1-bromo-4, 5-dichloro-2- (prop-2-en-1-yloxy) benzene (example 6, step b) (0.97 g, 3.43 mmol) in THF (5 mL) at 0 deg.C under a nitrogen atmosphere was added dropwisei-PrMgCl (1.71 mL, 3.42 mmol, 2M in THF). The resulting solution was stirred at 0 ℃ for 30 minutes under nitrogen atmosphere. Adding 5- [ methoxy (methyl) carbamoyl group to the above mixture at 0 ℃ under nitrogen atmosphere]-2-azabicyclo [ alpha ], [ alpha ] 2-aza ], [ alpha ] and [ alpha ], [ alpha ] a2.2.1]A solution of tert-butyl heptane-2-carboxylate (0.65 g, 2.29 mmol) in THF (2 mL). The resulting solution was stirred at room temperature under nitrogen for 1 hour. The reaction was quenched with saturated NH at 0 deg.C₄Aqueous Cl (20 mL) was quenched. The reaction mixture was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (4/1) in the form of a yellow oil The 5- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl group is obtained]-2-azabicyclo [ alpha ], [ alpha ] 2-aza ], [ alpha ] and [ alpha ], [ alpha ] a2.2.1]Heptane-2-carboxylic acid tert-butyl ester (0.15 g, 20%): C₂₁H₂₅Cl₂NO₄ [M + H - 15]⁺Calculated lcms (esi): 411, 413 (3: 2), found 411, 413 (3: 2); ¹H NMR (400 MHz, CDCl₃) δ 7.77 (s, 1H), 7.08 (s, 1H), 6.12-6.00 (m, 1H), 5.48-5.39 (m, 2H), 4.65 (d, J = 5.4 Hz, 2H), 4.28-4.23 (m, 1H), 3.51 (dd, J = 8.8, 5.5 Hz, 1H), 3.30 (dd, J = 9.8, 3.5 Hz, 1H), 3.12 (d, J = 9.8 Hz, 1H), 2.80-2.75 (m, 1H), 2.09-2.02 (m, 1H), 1.95-1.87 (m, 1H), 1.66-1.55 (m, 2H), 1.49 (s, 9H)。

step b:

to a stirred mixture of 5- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl at room temperature]-2-azabicyclo [ alpha ], [ alpha ] 2-aza ], [ alpha ] and [ alpha ], [ alpha ] a2.2.1]To a solution of tert-butyl heptane-2-carboxylate (0.15 g, 0.35 mmol) and 2-methylpropane-2-sulfinamide (85 mg, 0.70 mmol) in THF (3 mL) was added Ti (OEt)₄(0.80 g, 3.52 mmol). The resulting mixture was stirred at 70 ℃ for 16 hours under nitrogen atmosphere. The reaction was quenched with saturated NaHCO₃Aqueous solution (10 mL) was quenched at room temperature. The resulting mixture was filtered. The filter cake was washed with EA (5X 20 mL). Concentrating the filtrate under reduced pressure to obtain 5- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] as yellow oil][ (2-methylpropane-2-sulfinyl) imino]Methyl radical]-2-azabicyclo [ alpha ], [ alpha ] 2-aza ], [ alpha ] and [ alpha ], [ alpha ] a2.2.1]Tert-butyl heptane-2-carboxylate (0.22 g, crude), which was used in the next step without further purification: c₂₅H₃₄Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 529, 531 (3: 2), found 529, 531 (3: 2);

step c:

to a stirred 5- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl group at room temperature ][ (2-methylpropane-2-sulfinyl) imino ] methane]Methyl radical]-2-azabicyclo [ alpha ], [ alpha ] 2-aza ], [ alpha ] and [ alpha ], [ alpha ] a2.2.1]To a solution of tert-butyl heptane-2-carboxylate (0.22 g, 0.42 mmol) in THF (3 mL) was added NaBH₄(31 mg, 0.83 mmol). The resulting mixture was stirred at room temperature for 1 hour. Reacting with saturated NH₄Aqueous Cl solution(20 mL) was quenched at room temperature. The reaction mixture was extracted with EA (3X 20 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 5- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] in the form of a yellow oil][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]-2-azabicyclo [ alpha ], [ alpha ] 2-aza ], [ alpha ] and [ alpha ], [ alpha ] a2.2.1]Heptane-2-carboxylic acid tert-butyl ester (0.18 g, 90% of two steps in total): C₂₅H₃₆Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 531, 533 (3: 2), found 531, 533 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.50 (d, J = 18.3 Hz, 1H), 7.17 (dd, J = 12.9, 2.8 Hz, 1H), 6.22-6.01 (m, 1H), 5.55-5.39 (m, 1H), 5.39-5.26 (m, 1H), 4.71-4.56 (m, 3H), 4.56-4.44 (m, 1H), 4.38-4.18 (m, 1H), 4.17-4.04 (m, 1H), 3.18-2.98 (m, 1H), 2.92-2.74 (m, 1H), 2.36-2.05 (m, 2H), 1.81-1.55 (m, 2H), 1.52-1.41 (m, 9H), 1.25-1.18 (m, 9H)。

step d:

reacting 5- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]-2-azabicyclo [ alpha ], [ alpha ] 2-aza ], [ alpha ] and [ alpha ], [ alpha ] a2.2.1]A solution of tert-butyl heptane-2-carboxylate (0.18 g, 0.34 mmol) in TFA (1 mL) and DCM (5 mL) was stirred at room temperature for 30 min. The reaction was quenched with saturated NaHCO₃Aqueous solution (10 mL) was quenched and saturated NaHCO at 0 deg.C₃The aqueous solution was neutralized to pH 7. The resulting mixture was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na ₂SO₄And (5) drying. Filtering, concentrating the filtrate under reduced pressure to obtain yellow oilN- [ 2-azabicyclo [2 ], [2.2.1]Heptane-5-yl [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]2-methylpropane-2-sulfinamide (0.28 g, crude), which was used in the next step without further purification: c₂₀H₂₈Cl₂N₂O₂S [M + H]⁺Calculated lcms (esi): 431 and 433 (3: 2), found 431 and 433 (3: 2).

Step e:

stirring at room temperature (4)R)-2,2To a solution of-dimethyl-1, 3-dioxolane-4-carboxylic acid (0.14 g, 0.97 mmol) and HATU (0.37 g, 0.97 mmol) in DMF (5 mL) was addedN[ 2-azabicyclo [2 ], [2.2.1]Heptane-5-yl [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]-2-methylpropane-2-sulfinamide (0.28 g, 0.65 mmol) and Et₃N (0.13 g, 1.30 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction was purified by reverse phase chromatography eluting with 55% aqueous ACN (plus 0.05% TFA) to afford as a yellow oilN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([2-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]-2-azabicyclo [ alpha ], [ alpha ] 2-aza ], [ alpha ] and [ alpha ], [ alpha ] a2.2.1]Heptane-5-yl radical]) Methyl radical]2-methylpropane-2-sulfinamide (0.12 g, 63% of two-step total): C₂₆H₃₆Cl₂N₂O₅S [M + H]⁺Calculated lcms (esi): 559, 561 (3: 2), found 559, 561 (3: 2).

Step f:

at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([2-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]-2-azabicyclo [ alpha ], [ alpha ] 2-aza ], [ alpha ] and [ alpha ], [ alpha ] a2.2.1]Heptane-5-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide (0.12 g, 0.21 mmol) and Pd (PPh)₃)₄ (3 mg, 0.002 mmol) in THF (5 mL) NaBH was added₄(16 mg, 0.43 mmol). The resulting mixture was stirred at room temperature for 0.5 hour. Reacting with saturated NH₄Aqueous Cl (0.5 mL) was quenched at room temperature. Concentrating the obtained mixture under reduced pressure to obtain brown solidN- [ (4, 5-dichloro-2-hydroxyphenyl) ([2- [ (4) ]R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]-2-azabicyclo [ alpha ], [ alpha ] 2-aza ], [ alpha ] and [ alpha ], [ alpha ] a2.2.1]Heptane-5-yl radical]) Methyl radical]2-methylpropane-2-sulfinamide (0.10 g, crude), which was used in the next step without further purification: c₂₃H₃₂Cl₂N₂O₅S [M + H]⁺Calculated lcms (esi): 519, 521 (3: 2), found 519, 521 (3: 2).

Step g:

will be provided withN- [ (4, 5-dichloro-2-hydroxyphenyl) ([2- [ (4) ]R) -2, 2-dimethyl-1, 3-dioxolaneAlkyl-4-carbonyl]-2-azabicyclo [ alpha ], [ alpha ] 2-aza ], [ alpha ] and [ alpha ], [ alpha ] a2.2.1]Heptane-5-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide (0.10 g) in aqueous HCl (4)N,1 mL) and dioxane (1 mL) was stirred at room temperature for 30 minutes. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: a Xselect CSH OBD column 30 × 150 mm 5 μm n; mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 20% B to 40% B in 7 minutes; a detector: UV 254/220 nm; retention time: RT (reverse transcription) ₁7.03 minutes; RT (reverse transcription)₂10.12 minutes.

The fractions containing the desired product were collected at 7.03 minutes and concentrated under reduced pressure to give compound 315 ((2) as a pale pink solidR)-1-[5-[(R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]-2-azabicyclo [ alpha ], [ alpha ] 2-aza ], [ alpha ] and [ alpha ], [ alpha ] a2.2.1]Heptane-2-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid) (7.2 mg, 7% of a two-step sum) C₁₆H₂₀Cl₂N₂O₄ [M + H]⁺Calculated lcms (esi): 375, 377 (3: 2), found 375, 377 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.49 (s, 1H), 7.07 (d, J = 1.8 Hz, 1H), 4.65-4.47 (m, 1H), 4.36-4.11 (m, 2H), 3.75-3.57 (m, 2H), 3.55-3.45 (m, 1H), 3.27-3.11 (m, 1H), 2.85-2.72 (m, 1H), 2.66-2.51 (m, 1H), 1.86-1.56 (m, 3H), 1.40-1.16 (m, 1H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -76.96.

fractions containing the desired product were collected at 10.12 minutes and concentrated under reduced pressure to give compound 316 ((2) as a purple solidR)-1-[5-[(S) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]-2-azabicyclo [ alpha ], [ alpha ] 2-aza ], [ alpha ] and [ alpha ], [ alpha ] a2.2.1]Heptane-2-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid) (8.3 mg, 7% of two steps in total) C₁₆H₂₀Cl₂N₂O₄ [M + H]⁺Calculated lcms (esi): 375, 377 (3: 2), found 375, 377 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.51 (d, J = 2.5 Hz, 1H), 7.11 (d, J = 1.5 Hz, 1H), 4.79-4.60 (m, 1H), 4.40-4.13 (m, 2H), 3.81-3.59 (m, 2H), 3.56-3.45 (m, 1H), 3.04 (dd, J =27.2, 11.2 Hz, 1H), 2.52-2.39 (m, 1H), 2.24-2.05 (m, 2H), 1.85-1.55 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.11.

example 244 Compound 317 ((2)R)-1-[4-[(R) -amino (4-bromo-5-chloro-2-hydroxyphenyl) methyl]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid)

Step a:

stirred at 0 ℃ under nitrogen atmosphereN-[(R) - (4-bromo-5-chloro-2-methoxyphenyl) ([1- [ (4)R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-4-yl radical]) Methyl radical]-2-methylpropane-2-sulfinamide (intermediate 23, example 23) (40 mg, 0.07 mmol) in DCM (0.6 mL) was added BBr dropwise ₃(0.3 mL). The reaction mixture was stirred at 0 ℃ for 30 minutes. The resulting mixture was quenched with water (5 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge Prep C18 OBD column, 5 μm, 19 × 150 mm; a mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 10% B to 35% B in 7 minutes; a detector: 220 nm; retention time: 6.10 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 317 ((2)R)-1-[4-[(R) -amino (4-bromo-5-chloro-2-hydroxyphenyl) methyl]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid in the form of a pale yellow solid) (3.9 mg, 10%): C₁₅H₂₀BrClN₂O₄ [M + H]⁺Calculated lcms (esi): 407, 409 (2: 3), found 407, 409 (2: 3);¹H NMR (400 MHz, CD₃OD) δ 7.43 (s, 1H), 7.25 (s, 1H), 4.58 (dd, J = 53.9, 13.6 Hz, 2H), 4.33-4.02 (m, 2H), 3.67 (d, J = 22.6 Hz, 2H), 3.09 (dt, J = 42.2, 12.2 Hz, 1H), 2.67 (dt, J =42.3, 12.9 Hz, 1H), 2.38 (s, 1H), 2.01 (d, J = 12.1 Hz, 1H), 1.46-1.12 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -76.87.

example 245 combinationSubstance 326 ((2)R)-1-[(2S,4R)-4-[(R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]-2-methylpiperidin-1-yl]-2, 3-dihydroxypropan-1-one trifluoroacetic acid); compound 327 ((2)R)-1-[(2R,4S)-4-[(R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]-2-methylpiperidin-1-yl]-2, 3-dihydroxypropan-1-one trifluoroacetic acid)

Step a:

to a stirred mixture of 4- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl group containing two trans isomers at room temperature under nitrogen ]Tert-butyl (2-methylpiperidine-1-carboxylate (intermediate 43b, example 43) (0.30 g, 0.70 mmol) and tert-butanesulfinamide (0.13 g, 1.05 mmol) in THF (5 mL) were added Ti (OEt)₄(1.60 g, 7.00 mmol). The reaction was stirred at 70 ℃ for 16 hours. After cooling to room temperature, the reaction was quenched with saturated Na₂CO₃Aqueous solution (30 mL) was quenched. The resulting mixture was filtered through celite (celite), then the filtrate was diluted with EA (30 mL) and water (30 mL), and the aqueous layer was extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography, eluting with PE/EA (5/1), to obtain 4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] containing two trans isomers as yellow solid]([[(S) -2-methylpropan-2-sulfinyl]Imino radical]) Methyl radical]-2-methylpiperidine-1-carboxylic acid tert-butyl ester (0.30 g, 73%): C₂₅H₃₆Cl₂N₂O₄S[M + Na]⁺Calculated lcms (esi): 551, 552 (3: 2), found 551, 553 (3: 2);¹H NMR (400 MHz, CDCl₃)δ 7.18 (s, 1H), 6.98 (s, 1H), 6.10-5.89 (m, 1H), 5.45-5.36 (m, 1H), 5.32 (d, J = 10.6 Hz, 1H), 4.63-4.40 (m, 3H), 4.16-3.94 (m, 1H), 2.93-2.76 (m, 2H), 1.93-1.80 (m, 1H), 1.79-1.65 (m, 1H), 1.65-1.48 (m, 2H), 1.47 (s, 9H), 1.23 (s, 9H), 1.13 (dd, J = 15.2, 6.9 Hz, 3H)。

step b:

4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] containing two trans isomers stirred at-70 ℃ under nitrogen atmosphere]([[(S) -2-methylpropan-2-sulfinyl]Imino radical ]) Methyl radical]To a solution of tert-butyl (0.20 g, 0.38 mmol) of-2-methylpiperidine-1-carboxylate in THF (5 mL) was added DIBAL-H (0.56 mL, 0.564 mmol, 1M in toluene). The reaction was stirred at-70 ℃ for 2 hours. Saturated NH is used for reaction₄Aqueous Cl (2 mL) was quenched and then diluted with EA (30 mL) and water (30 mL). The aqueous layer was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (2X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to obtain 4- [ (r) ((r)) containing two trans isomers in the form of a yellow oilR) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]-tert-butyl 2-methylpiperidine-1-carboxylate (0.30 g, crude), which is used in the next step without further purification: c₂₅H₃₈Cl₂N₂O₄S[M + H]⁺Calculated lcms (esi): 533, 535 (3: 2), measured 533, 535 (3: 2).

Step c:

4- [ (ii) containing two trans isomers, stirred at room temperatureR) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]To a solution of tert-butyl-2-methylpiperidine-1-carboxylate (0.30 g, 0.56 mmol) in DCM (5 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 0.5 h. The reaction was saturated with Na ₂CO₃Aqueous solution (20 mL) was quenched with saturated Na₂CO₃The aqueous solution (30 mL) was neutralized to pH 7. The resulting solution was diluted with EA (30 mL) and water (30 mL), and the aqueous layer was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give a yellow oil containing two trans isomersS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][ 2-methylpiperidin-4-yl group]Methyl radical]-2-methylpropan-2-ylideneSulfonamide (0.25 g, crude), which was used in the next step without further purification: c₂₀H₃₀Cl₂N₂O₂S [M + H]⁺Calculated lcms (esi): 433, 435, (3: 2), found 433, 435 (3: 2).

Step d:

stirring at room temperature (4R) (3 mL) of a solution of (e) -2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid (0.13 g, 0.87 mmol) and HATU (0.33 g, 0.87 mmol) in DMF (3 mL) was added (containing two trans isomers)S)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][ 2-methylpiperidin-4-yl group]Methyl radical]2-methylpropane-2-sulfinamide (0.25 g, 0.58 mmol) and Et₃N (0.12 g, 1.15 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was purified by reverse phase chromatography eluting with 52% aqueous ACN (plus 0.05% TFA) to give a pale yellow oil containing the two trans isomers (ii) ((iii)) S)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]-2-methylpiperidin-4-yl]Methyl radical]2-methylpropane-2-sulfinamide (0.15 g, 71% of the total of the three steps): C₂₆H₃₈Cl₂N₂O₅S [M + H]⁺Lcms (esi) calculated value of (a): 561, 563 (3: 2), found 561, 563 (3: 2).

Step e:

to a stirred mixture at room temperature of (A) containing two trans isomersS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]-2-methylpiperidin-4-yl]Methyl radical]-2-methylpropane-2-sulfinamide (0.15 g, 0.27 mmol) and Pd (PPh)₃)₄ (31 mg, 0.03 mmol) in THF (5 mL) NaBH was added₄(20 mg, 0.53 mmol). The reaction was stirred at room temperature for 30 minutes. Reacting with saturated NH₄Aqueous Cl (1 mL) was quenched and concentrated under reduced pressure to give a light brown oil containing two trans isomersS)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) [1- [ (4)R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]-2-methylpiperidin-4-yl]Methyl radical]2-methylpropane-2-sulfinamide (0.10 g, crude), which was used in the next step without further purification: c₂₃H₃₄Cl₂N₂O₅S [M + H]⁺Calculated lcms (esi): 521, 523 (3: 2), found 521, 523 (3: 2).

Step f:

to a stirred mixture at room temperature of (A) containing two trans isomersS)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) [1- [ (4)R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]-2-methylpiperidin-4-yl]Methyl radical](iii) -2-methylpropane-2-sulfinamide (0.10 g, 0.19 mmol) in 1, 4-dioxane (2 mL) to which was added aqueous HCl (4)N1 mL). The reaction was stirred at room temperature for 1 hour. The reaction was performed with EA (20 mL) and HCl (1)N20 mL). The organic layer was washed with aqueous HCl (1)N2X 20 mL). The combined aqueous layers were concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xselect CSH OBD column 30X 150 mm 5 μm; mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 8% B to 17% B in 9 minutes; a detector: UV 254/220 nm; retention time: RT (reverse transcription)₁8.47 min, RT₂9.32 minutes.

The fractions containing the desired product were collected at 8.47 minutes and concentrated under reduced pressure to afford compound 326 ((2) as an off-white solidR)-1-[(2S,4R)-4-[(R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]-2-methylpiperidin-1-yl]-2, 3-dihydroxypropan-1-one trifluoroacetic acid) (24 mg, 18% of a two-step total) C₁₆H₂₂Cl₂N₂O₄ [M + H]⁺Calculated lcms (esi): 377, 379 (3: 2), found 377, 379 (3: 2); ¹H NMR (400 MHz, CD₃OD)δ 7.43 (d, J = 4.0 Hz, 1H), 7.09 (s, 1H), 5.09-4.96 (m, 1H), 4.67-4.26 (m, 2H), 4.16-4.02 (m, 1H), 3.92 (d, J = 14.1 Hz, 1H), 3.73-3.52 (m, 2H), 3.25-2.74 (m, 1H), 2.64-2.49 (m, 1H), 1.93 (t, J = 12.0 Hz, 1H), 1.64-1.40 (m, 1H), 1.31 (dd, J = 46.9, 7.0 Hz, 3H), 1.23-1.03 (m, 1H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.02.

The fractions containing the desired product were collected at 9.32 minutes and concentrated under reduced pressure to give compound 327 ((2) as an off-white solidR)-1-[(2R,4S)-4-[(R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]-2-methylpiperidin-1-yl]-2, 3-dihydroxypropan-1-one trifluoroacetic acid) (32 mg, 24% of a two-step total) C₁₆H₂₂Cl₂N₂O₄ [M + H]⁺Calculated lcms (esi): 377, 379 (3: 2), found 377, 379 (3: 2);¹H NMR (400 MHz, CD3OD)δ 7.41 (d, J = 2.1 Hz, 1H), 7.09 (s, 1H), 4.86-4.77 (m, 1H), 4.59-4.42 (m, 2H), 4.09 (dd, J = 14.9, 9.8 Hz, 2H), 3.78-3.55 (m, 2H), 3.30-2.83 (m, 1H), 2.78-2.53 (m, 1H), 2.07-1.85 (m, 1H), 1.50-1.29 (m, 1H), 1.29-1.04 (m, 4H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -76.96.

example 246 Compound 328 ((2)R) -1- [4- [ amino (3, 4-dichloro-2-fluoro-6-hydroxyphenyl) methyl group]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid)

Step a:

to a solution of diisopropylamine (2.71 g, 2.67 mmol) in THF (10 mL) at-65 deg.C was added over 10 minutes under a nitrogen atmospherenBuLi (1.28 mL, 3.213 mmol, 2.5 mol/L in hexane). After the addition, the reaction solution was stirred for 30 minutes and then added dropwise at-65 ℃ under a nitrogen atmosphereN,NA solution of 3, 4-dichloro-5-fluorophenyl diethylcarbamate (example 18, step c) (0.50 g, 1.78 mmol) in THF (3). After stirring for another 35 minutes, 4- [ [ (2-methylpropane-2-sulfinyl) imino ] was added dropwise to the resulting mixture at-65 ℃ over 10 minutes]Methyl radical]A solution of tert-butyl piperidine-1-carboxylate (intermediate 11, example 11) (0.85 g, 2.67 mmol) in THF (3 mL). The reaction mixture was stirred at-65 ℃ for an additional 1 hour under nitrogen. The resulting mixture was quenched with water (30 mL) at-65 ℃ and extracted with EA (2X 70 mL). The combined organic layers were washed with brine (2X 10 mL) Washing with anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel and eluted with PE/EA (5/1) to give 4- ([3, 4-dichloro-6- [ (diethylcarbamoyl) oxy) as a yellow oil]-2-fluorophenyl][ (2-methylpropane-2-sulfinyl) amino group]Methyl) piperidine-1-carboxylic acid tert-butyl ester (0.57 g, 48%): C₂₆H₄₀Cl₂FN₃O₅S [M + H]⁺Lcms (esi) calculated value of (a): 596, 598 (3: 2), found 596, 598 (3: 2).

Step b:

to 4- ([3, 4-dichloro-6- [ (diethylcarbamoyl) oxy group at room temperature]-2-fluorophenyl group][ (2-methylpropane-2-sulfinyl) amino]Methyl) piperidine-1-carboxylic acid tert-butyl ester (0.57 g, 0.96 mmol) in MeOH (5 mL) NaOH (0.38 g, 9.58 mmol) was added in portions. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (20 mL) at room temperature and acidified to pH 4 with citric acid. The resulting solution was extracted with EA (2X 100 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 4- [ (3, 4-dichloro-2-fluoro-6-hydroxyphenyl) [ (2-methylpropane-2-sulfinyl) amino]Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester (0.56 g, 1.13 mmol). The crude product was used without further purification in the subsequent step: c ₂₁H₃₁Cl₂FN₂O₄S [M + H]⁺Lcms (esi) calculated value of (a): 497, 499 (3: 2), found 497, 499 (3: 2).

Step c:

to 4- [ (3, 4-dichloro-2-fluoro-6-hydroxyphenyl) [ (2-methylpropane-2-sulfinyl) amino ] at room temperature]Methyl radical]A solution of piperidine-1-carboxylic acid tert-butyl ester (crude) in DCM (10 mL) was added TFA (2 mL) dropwise. The reaction solution was stirred at room temperature for 1 hour. The resulting solution was diluted with saturated NaHCO₃The aqueous solution was adjusted to pH 9 and extracted with EA (2X 200 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. Filtering, and concentrating the filtrate under reduced pressure to obtainN- [ (3, 4-dichloro-2-fluoro-6-hydroxyphenyl) (piperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide (0.56 g, 1.41 mmol). The crude product was used without further purification in the subsequent step: c₁₆H₂₃Cl₂FN₂O₂S [M + H]⁺Calculated lcms (esi): 397, 399 (3: 2), found 397, 399 (3: 2).

Step d:

stirring at room temperature (R) To a solution of-2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid (0.30, 2.11 mmol) and HATU (1.07 g, 2.82 mmol) in DMF (5 mL) was added Et₃N (0.43 g, 4.23 mmol) and N- [ (3, 4-dichloro-2-fluoro-6-hydroxyphenyl) (piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.56 g, 1.41 mmol). After stirring at room temperature for 2 hours, the reaction solution was quenched with water (30 mL) at room temperature and extracted with EA (3X 100 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purifying the residue by reverse phase chromatography, eluting with 70% aqueous ACN solution to obtain a yellow oilN- [ (3, 4-dichloro-2-fluoro-6-hydroxyphenyl) [1- (2, 2-dimethyl-1, 3-dioxolane-4-carbonyl) piperidin-4-yl]Methyl radical]2-methylpropane-2-sulfinamide (0.28 g, 42% of the total of the three steps): C₂₂H₃₁Cl₂FN₂O₅S [M + H]⁺Calculated lcms (esi): 525, 527 (3: 2), found 525, 527 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 6.85 (s, 1H), 4.63-4.41 (m, 2H), 4.20-4.00 (m,2H), 3.75-3.55 (m, 2H), 3.20-2.94 (m, 1H), 2.79-2.50 (m, 1H), 2.43-2.25 (m, 1H), 2.08-1.96 (m, 1H), 1.64-1.28 (m, 3H), 1.31-1.19 (m, 6H), 1.12 (s, 9H)。

step e:

at room temperature with stirringN- [ (3, 4-dichloro-2-fluoro-6-hydroxyphenyl) [1- (2, 2-dimethyl-1, 3-dioxolane-4-carbonyl) piperidin-4-yl]Methyl radical]-2-methylpropane-2-sulfinamide (0.28 g, 0.53 mmol) in THF (4 mL) aqueous HCl (6) was addedN2 mL). The reaction solution was stirred at room temperature for 1 hour. The resulting solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xselect CSH OBD column 30 x 150 mm, 5 μm; mobile phase A: water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 7% B to 22% B in 7 minutes; a detector: UV 220 nm; retention time: 6.25 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 328 as an off-white solid ((2) R) -1- [4- [ amino (3, 4-dichloro-2-fluoro-6-hydroxyphenyl) methyl]Piperidin-1-yl]-2, 3-dihydroxypropan-1-one trifluoroacetic acid) (106 mg, 52%): C₁₅H₁₉Cl₂FN₂O₄ [M + H]⁺Lcms (esi) calculated value of (a): 381, 383 (3: 2), found 381, 383 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 6.98 (d, J = 1.8 Hz, 1H), 4.72-4.34 (m, 3H), 4.21 (dd, J = 58.5, 13.9 Hz, 1H), 3.80-3.56 (m, 2H), 3.23-2.95 (m, 1H), 2.79-2.58 (m, 1H), 2.54-2.36 (m, 1H), 2.04-1.95 (m, 1H) 1.57-1.06 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -76.85, 113.17.

example 247 Compound 329 ((2)R)-1-[(3R)-3-[(R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid); compound 330 ((2)R)-1-[(3R)-3-[(S) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid)

Step a:

to a stirred solution of 1-bromo-4, 5-dichloro-2- (prop-2-en-1-yloxy) benzene (example 6, step b) (0.52 g, 1.83 mmol) in THF (5 mL) at 0 deg.C under a nitrogen atmosphere was added dropwisei-PrMgCl (1 mL, 2.00 mmol, 2M in THF). After stirring for 30 minutes at 0 deg.C, (3) was added at 0 deg.C under nitrogen atmosphereR) A solution of tert-butyl (3-formylpiperidine-1-carboxylate (0.30 g, 1.41 mmol) in THF (3 mL) was added dropwise to the resulting mixture. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. Reacting with saturated NH₄Aqueous Cl (40 mL) was quenched. The resulting mixture was extracted with EA (2X 10 mL). To be combined withThe organic layer was washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄Dried, filtered and concentrated under reduced pressure. Purifying the residue by silica gel column chromatography, eluting with EA to obtain (3R) -3- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] as colorless oil ](hydroxy) methyl group]Piperidine-1-carboxylic acid tert-butyl ester (0.40 g, 68%): C₂₀H₂₇Cl₂NO₄ [M + H]⁺Calculated lcms (esi): 416, 418 (3: 2), found 416, 418 (3: 2).

Step b:

to (3R) -3- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] at 0 deg.C](hydroxy) methyl group]To a solution of tert-butyl piperidine-1-carboxylate (0.40 g, 0.96 mmol) in DCM (10 mL) was added dess-martin reagent (0.49 g, 1.15 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture obtained is treated with a cosolvent NaHCO₃Aqueous solution/Na₂SO₃Aqueous solution (20 mL, v/v = 1/1). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA/PE (1/1) to give (3) as a pale yellow oilR) -3- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl]Piperidine-1-carboxylic acid tert-butyl ester (0.36 g, 90%): C₂₀H₂₅Cl₂NO₄ [M + H]⁺Calculated lcms (esi): 414, 416 (3: 2), found 414, 416 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.69 (s, 1H), 7.07 (s, 1H), 6.11-6.01 (m, 1H), 5.51-5.33 (m, 2H), 4.73-4.57 (m, 2H), 4.34-3.85 (m, 2H), 3.47-3.32 (m, 1H), 2.88-2.71 (m, 2H), 2.04-1.92 (m, 2H), 1.76-1.71 (m, 2H), 1.48 (s, 9H)。

step c:

stirring under nitrogen atmosphere (3)R) -3- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl]To a solution of tert-butyl piperidine-1-carboxylate (0.36 g, 0.87 mmol) and 2-methylpropane-2-sulfinamide (0.16 g, 1.30 mmol) in THF (20 mL) was added Ti (OEt) in one portion ₄(1.98 g, 8.69 mmol). The reaction solution was stirred at 80 ℃ for 48 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was poured into a flaskAnd NaHCO₃In aqueous solution (100 mL), the solid was separated, then the mixture was filtered and the filtrate was extracted with EA (2X 50 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give (3) as a pale yellow oilR) -3- [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][ (2-methylpropane-2-sulfinyl) imino]Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester (0.40 g, crude): C₂₄H₃₄Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 517, 519 (3: 2), found 517, 519 (3: 2).

Step d:

stirred downwards at 0 ℃ (3)R) -3- [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][ (2-methylpropane-2-sulfinyl) imino]Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester (0.40 g, 0.77 mmol) in MeOH (10 mL) NaBH was added portionwise₄(59 mg, 1.55 mmol). The resulting mixture was stirred at room temperature for 2 hours. Reacting with saturated NH₄Aqueous Cl (50 mL) was quenched and extracted with EA (3X 30 mL). Combining the combined organic layers over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give (3) as a pale yellow oil R) -3- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] carbonyl][ (2-methylpropane-2-sulfinyl) amino group]Methyl radical]Piperidine-1-carboxylic acid tert-butyl ester (0.40 g, crude): C₂₄H₃₆Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 519, 521 (3: 2), found 519, 521 (3: 2).

Step e:

stirring at room temperature (3)R) -3- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]To a solution of tert-butyl piperidine-1-carboxylate (0.40 g, 0.77 mmol) in DCM (4 mL) was added TFA (1 mL). The reaction solution was stirred at room temperature for 1 hour. The resulting solution was taken up in saturated NaHCO₃The aqueous solution was basified to pH 8. The resulting mixture was extracted with DCM (3X 20 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the mixture is filteredConcentrating the filtrate under reduced pressure to obtain light yellow oilN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][(3R) -piperidin-3-yl]Methyl radical]2-methylpropane-2-sulfinamide (260 mg, crude): C₁₉H₂₈Cl₂N₂O₂S [M + H]⁺Calculated lcms (esi): 419, 421 (3: 2), found 419, 421 (3: 2).

Step f:

to stirred HATU (0.35 g, 0.93 mmol) and (4) at room temperatureR) Et was added to a solution of (0.14 g, 0.93 mmol) 2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid in DMF (4 mL) ₃N (0.13 g, 1.24 mmol) and N- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][(3R) -piperidin-3-yl]Methyl radical]-2-methylpropane-2-sulfinamide (0.26 g, 0.62 mmol). After stirring at room temperature for 2 hours, the resulting solution was quenched with water (30 mL) and extracted with EA (3X 20 mL). The combined organic layers were washed with brine (3X 15 mL) and dried over anhydrous Na₂SO₄And (5) drying. Filtering, concentrating the filtrate under reduced pressure to obtain light yellow oilN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][(3R)-1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-3-yl radical]Methyl radical]2-methylpropane-2-sulfinamide (0.35 g, crude): C₂₅H₃₆Cl₂N₂O₅ [M + H]⁺Calculated lcms (esi): 547, 549 (3: 2), found 547, 549 (3: 2).

Step g:

under nitrogen atmosphere at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl][(3R) -1- [ (4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-3-yl radical]Methyl radical]-2-methylpropane-2-sulfinamide (0.35 g, 0.64 mmol) and Pd (PPh)₃)₄(15 mg, 0.01 mmol) in THF (5 mL) NaBH was added portionwise₄(48 mg, 1.28 mmol). The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was washed with saturated NH at 0 deg.C₄Aqueous Cl (5 mL) was quenched and extracted with EA (3X 20 mL). The combined organic layers were washed with brine (2X 10 mL) and dried over anhydrous Na ₂SO₄And (5) drying. For treatingAfter filtration, the filtrate was concentrated under reduced pressure to obtain a pale yellow oilN- [ (4, 5-dichloro-2-hydroxyphenyl) [ (3)R)-1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-3-yl radical]Methyl radical]2-methylpropane-2-sulfinamide (0.40 g, crude): C₂₂H₃₂Cl₂N₂O₅ [M + H]⁺Calculated lcms (esi): 507, 509 (3: 2), found 507, 509 (3: 2).

Step h:

at room temperature with stirringN- [ (4, 5-dichloro-2-hydroxyphenyl) [ (3)R)-1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Piperidin-3-yl radical]Methyl radical]-2-methylpropane-2-sulfinamide (0.40 g, crude) in THF (10 mL) aqueous HCl (4) was added dropwiseN5 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xselect CSH OBD column 30 × 150 mm, 5 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 5% B to 20% B in 7 minutes; a detector: UV 220 nm; retention time: RT (reverse transcription)₁6.10 minutes; RT (reverse transcription)₂6.72 minutes.

The faster eluting enantiomer was obtained as compound 330 ((2) as an off-white solidR)-1-[(3R)-3-[(S) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group ]Piperidin-1-yl]-2, 3-dihydroxypropan-1-one trifluoroacetic acid) (23 mg, 7% in 6 steps total): C₁₅H₂₀Cl₂N₂O₄ [M + H]⁺Calculated lcms (esi): 363, 365 (3: 2), measured 363, 365 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.46 (d, J = 14.1 Hz, 1H), 7.11 (d, J = 12.6 Hz, 1H), 4.57-4.41 (m, 1H), 4.23 (d, J = 9.9 Hz, 1H), 4.17-3.73 (m, 2H), 3.64 (qt, J = 18.4, 8.7 Hz, 2H), 2.96 (dt, J = 117.9, 12.3 Hz, 1H), 2.57 (dt, J = 56.1, 12.1 Hz, 1H), 2.42-2.07 (m, 2H), 1.99-1.83 (m, 1H), 1.70-140 (m, 2H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -76.99.

obtained as an off-white solidTo the slower eluting enantiomer as compound 329 ((2)R)-1-[(3R)-3-[(R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one trifluoroacetic acid) (48.9 mg, 16% of the total of 6 steps): C₁₅H₂₀Cl₂N₂O₄ [M + H]⁺Calculated lcms (esi): 363, 365 (3: 2), measured 363, 365 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.44 (d, J = 8.7 Hz, 1H), 7.09 (s, 1H), 4.62-4.58 (m, 1H), 4.43-4.19 (m, 1H), 4.11 (d, J = 13.7 Hz, 1H), 3.83-3.65 (m, 3H), 3.63-3.44 (m, 1H), 3.43-3.35 (m, 1H), 2.48-2.30 (m, 1H), 1.88-1.69 (m, 1H), 1.67-1.45 (m, 2H), 1.39-1.19 (m, 1H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.03.

example 248 Compound 331 ((2)R)-1-((3R,4R) -rel-4- ((R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) -3-methylpiperidin-1-yl) -2, 3-dihydroxypropan-1-one trifluoroacetic acid isomer 1); compound 332 ((2R) -1- ((3R,4R) -rel-4- ((R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) -3-methylpiperidin-1-yl) -2, 3-dihydroxypropan-1-one trifluoroacetic acid isomer 2)

Step a:

to a stirred 4- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl group at room temperature under nitrogen atmosphere]-3-methylpiperidine-1-carboxylic acid tert-butyl ester (cis isomer) (0.38 g, 0.88 mmol) and (CS) (iii) -2-methylpropane-2-sulfinamide (0.21 g, 1.77 mmol) in THF (5 mL) Ti (OEt)₄(2.00 g, 8.87 mmol). The resulting mixture was stirred at 70 ℃ for 16 hours under nitrogen atmosphere. After cooling to room temperature, the resulting mixture was taken up with saturated Na ₂CO₃Aqueous solution (30 mL) was quenched. A solid formed and was filtered, and the filter cake was washed with EA (3X 100 mL). The filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography, eluting with PE/EA (3/1), and obtaining 4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] as yellow oil]([[(S) -2-methylpropan-2-sulfinyl]Imino radical]) Methyl radical]3-methylpiperidine-1-carboxylic acid tert-butyl ester (0.24 g, 50%): C₂₅H₃₆Cl₂N₂O₄S[M + Na]⁺Calculated lcms (esi): 553, 555 (3: 2), found 553, 555 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.03-6.91 (m, 2H), 6.11-5.88 (m, 1H), 5.35-5.26 (m, 2H), 4.67-4.53 (m, 2H), 4.40-4.18 (m, 1H), 4.07-3.88 (m, 1H), 3.01-2.64 (m, 2H), 2.54-2.25 (m, 1H), 2.03-1.85 (m, 1H), 1.68-1.54 (m, 2H), 1.51-1.45 (m, 9H), 1.26-1.18 (m, 9H), 1.02 (d, J = 7.0 Hz, 3H)。

step b:

4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] stirred at-65 ℃ under nitrogen]([[(S) -2-methylpropan-2-sulfinyl]Imino radical]) Methyl radical]-3-methylpiperidine-1-carboxylic acid tert-butyl ester (0.24 g, 0.45 mmol) in THF (3 mL) DIBAL-H (0.11 mL, 0.80 mmol, 1M in toluene) was added dropwise. The resulting mixture was stirred at-65 ℃ for 3 hours under nitrogen. The reaction was quenched with saturated NH at room temperature₄Aqueous Cl (0.5 mL) was quenched and diluted with water (50 mL). The aqueous layer was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. Filtering, concentrating the filtrate under reduced pressure to obtain 4- [ ((R)) in the form of yellow oilR) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]-3-methylpiperidine-1-carboxylic acid tert-butyl ester (0.25 g, crude), which is used in the next step without further purification: c₂₅H₃₈Cl₂N₂O₄S[M + H]⁺Calculated lcms (esi): 533, 535 (3: 2), found 533, 535 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.01-6.81 (m, 2H), 6.19-5.90 (m, 1H), 5.40-5.31 (m, 2H), 4.82-4.48 (m, 3H), 4.39-4.21 (m, 1H), 4.06-3.77 (m, 1H), 2.90-2.56 (m, 2H), 2.56-2.40 (m, 1H), 1.83-1.64 (m, 1H), 1.63-1.53 (m, 2H), 1.51-1.43 (m, 9H), 1.09 (s, 9H), 0.83 (d, J = 6.9 Hz, 3H)。

step c:

4- [ (ii) to stirring at room temperatureR) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]To a mixture of tert-butyl-3-methylpiperidine-1-carboxylate (0.25 g, 0.47 mmol) in DCM (5 mL) was added TFA (1 mL). The resulting mixture was stirred at room temperature for 30 minutes. The reaction solution was saturated with NaHCO at 0 deg.C₃The aqueous solution was neutralized to pH 8 and diluted with water (50 mL). The aqueous layer was extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to obtain (A) in the form of a yellow oilS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](3-methylpiperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.2 g, crude), which was used in the next step without further purification: c₂₀H₃₀Cl₂N₂O₂S [M + H]⁺Calculated lcms (esi): 433, 435 (3: 2), found 433, 435 (3: 2)_； ¹H NMR (400 MHz, CDCl₃) δ 7.09-6.90 (m, 2H), 6.08-5.95 (m, 1H), 5.52-5.28 (m, 2H), 4.65-4.49 (m, 3H), 3.99-3.81 (m, 1H), 3.43-3.21 (m, 2H), 3.21-2.95 (m, 1H), 2.95-2.61 (m, 1H), 2.55-2.15 (m, 1H), 2.00-1.71 (m, 2H), 1.14-1.01 (m, 12H)。

Step d:

stirring at room temperature ( 4R) (2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid (0.10 g, 0.69 mmol) and HATU (0.26 g, 0.69 mmol) in DMF (3 mL) was addedS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](3-methylpiperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide (0.20 g, 0.46 mmol) and Et₃N (93 mg, 0.92 mmol). The resulting mixture was stirred at room temperature for 0.5 hour. The reaction was purified by reverse phase chromatography eluting with 40% aqueous ACN (plus 0.05% TFA) to afford (b) as a yellow oilS)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]-3-methylpiperidin-4-yl]) Methyl radical]2-methylpropane-2-sulfinamide (0.17 g, 67% of the total of the three steps): C₂₆H₃₈Cl₂N₂O₅S [M + H]⁺Calculated lcms (esi): 561, 563(3: 2), found 561, 563(3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.28-7.14 (m, 1H), 7.06-6.91 (m, 1H), 6.15-5.92 (m, 1H), 5.52-5.30 (m, 2H), 4.81-4.48 (m, 3H), 4.45-4.25 (m, 2H), 4.22-4.02 (m, 2H), 4.02-3.65 (m, 1H), 3.31-2.88 (m, 2H), 2.85-2.60 (m, 2H), 1.69-1.48 (m, 2H), 1.47-1.34 (m, 6H), 1.10 (s, 9H), 0.93-0.75 (m, 3H)。

step e:

stirring at room temperature (S)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]-3-methylpiperidin-4-yl]) Methyl radical]-2-methylpropane-2-sulfinamide (0.17 g, 0.30 mmol) and Pd (PPh)₃)₄(4 mg, 0.003 mmol) in THF (2 mL) NaBH was added₄(22 mg, 0.60 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The reaction was quenched with saturated NH at room temperature ₄Aqueous Cl (1 mL) was quenched. Concentrating the obtained mixture under reduced pressure to obtain (A)S)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) ([1- [ (s))4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]-3-methylpiperidin-4-yl]) Methyl radical]-2-methylpropane-2-sulfinamide (0.10 g, 63%) which was used in the next step without further purification: c₂₃H₃₄Cl₂N₂O₅S [M + H]⁺Calculated lcms (esi): 521, 523 (3: 2), found 521, 523 (3: 2).

Step f:

stirring at room temperature (S)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) ([1- [ (s))4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]-3-methylpiperidin-4-yl]) Methyl radical]To a mixture of (E) -2-methylpropane-2-sulfinamide (0.10 g, 0.19 mmol) in 1, 4-dioxane (1 mL) was added aqueous HCl (4)N,1 mL). The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: a Xselect CSH OBD column 30 × 150 mm 5 μm n; mobile phase A: water (adding 0.0)5% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 5% B to 20% B in 8.5 minutes; 220 nm; a detector: UV 254/220 nm; retention time: RT (reverse transcription)₁7.90 minutes, RT₂8.60 minutes.

The fractions containing the desired product were collected at 7.90 minutes and concentrated under reduced pressure to give compound 331 as an off-white solid ((2) R)-1-((3S,4S)-4-((R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) -3-methylpiperidin-1-yl) -2, 3-dihydroxypropan-1-one trifluoroacetic acid (37 mg, 25% of two-step total) C₁₆H₂₂Cl₂N₂O₄ [M + H]⁺Lcms (esi) calculated value of (a): 377, 379 (3: 2), found 377, 379 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.46 (s, 1H), 7.08 (s, 1H), 4.65-4.38 (m, 2H), 4.38-3.98 (m, 2H), 3.80-3.51 (m, 2H), 2.96 (t, J = 13.0 Hz, 1H), 2.83 (d, J = 13.0 Hz, 1H), 2.61-2.39 (m, 1H), 2.29-2.08 (m, 1H), 1.62-1.20 (m, 1H), 1.20-0.85 (m, 4H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.09.

the fractions containing the desired product were collected at 8.60 minutes and concentrated under reduced pressure to give compound 332 ((2) as an off-white solidR)-1-((3R,4R)-4-((R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl) -3-methylpiperidin-1-yl) -2, 3-dihydroxypropan-1-one trifluoroacetic acid (31 mg, 21% of two steps in total) C₁₆H₂₂Cl₂N₂O₄ [[M + H]⁺Lcms (esi) calculated value of (a): 377, 379 (3: 2), found 377, 379 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.54 (d, J = 5.6 Hz, 1H), 7.11 (s, 1H), 4.78-4.51 (m, 2H), 4.48-4.14 (m, 2H), 3.92-3.50 (m, 3H), 3.25-3.05 (m, 1H), 2.81-2.51 (m, 2H), 1.87-1.68 (m, 1H), 1.68-1.46 (m, 1H), 0.99-0.76 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.04.

example 249. Compound 333 ((2)R)-1-[4-[(R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Azepan-1-yl]-2, 3-dihydroxypropan-1-one trifluoroacetic acid isomer 1); compound 334 ((2)R)-1-[4-[(R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Azepan-1-yl]-2, 3-dihydroxypropan-1-one trifluoroacetic acid isomer 2

Step a:

to a stirred solution of 4-bromo-1, 2-dichloro-5- (prop-2-en-1-yloxy) cyclohexa-1, 3-diene (2.50 g, 8.80 mmol) in THF (25 mL) was added dropwise under a nitrogen atmosphere at 0 deg.Ci-PrMgCl (5.5 mL, 11.00 mmol, 2M in THF). The resulting solution was stirred at 0 ℃ for 30 minutes under nitrogen atmosphere. To the above mixture was added dropwise a solution of tert-butyl 4-formylazepane-1-carboxylate (1.00 g, 4.40 mmol) in THF (2 mL) at 0 deg.C over 5 minutes. The resulting solution was stirred at 0 ℃ for an additional 1 hour. The reaction was quenched with saturated NH at 0 deg.C ₄Aqueous Cl (50 mL) was quenched and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with PE/EA (1/1) to give 4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] in the form of a pale yellow oil](hydroxy) methyl group]N-azacycloheptane-1-carboxylic acid tert-butyl ester (0.60 g, 27%): C₂₁H₂₉Cl₂NO₄ [M + Na]⁺Calculated lcms (esi): 452, 454 (3: 2), found 452, 454 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.43 (d, J = 2.1 Hz, 1H), 6.94 (s, 1H), 6.08-5.93 (m, 1H), 5.47-5.30 (m, 2H), 4.77 (dd, J = 24.0, 6.2 Hz, 1H), 4.65-4.49 (m, 2H), 3.62-3.44 (m, 2H), 3.33-3.12 (m, 2H), 2.11-1.53 (m, 3H), 1.54-1.40 (m, 12H), 1.37-1.17 (m, 1H)。

step b:

to a stirred 4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl group at room temperature](hydroxy) methyl group]To a solution of azepane-1-carboxylic acid tert-butyl ester (0.60 g, 1.40 mmol) in DCM (5 mL) was added dess-martin reagent (0.12 g, 2.80 mmol) in portions. The resulting solution was stirred at room temperature for 2 hours. Reacting at room temperatureSaturated Na₂SO₃Aqueous solution (10 mL) was quenched. The resulting mixture was diluted with water (20 mL) and extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (5/1) to give 4- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl group as an off-white solid ]N-heptane-1-carboxylic acid tert-butyl ester (0.60 g, 80%) C₂₁H₂₇Cl₂NO₄ [M + Na]⁺Calculated lcms (esi): 450, 452 (3: 2), found 450, 452 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.67 (s, 1H), 7.06 (s, 1H), 6.13-5.97 (m, 1H), 5.51-5.33 (m, 2H), 4.64 (dt, J = 5.5, 1.5 Hz, 2H), 3.70-3.48 (m, 2H), 3.45-3.34 (m, 2H), 3.29-3.20 (m, 1H), 2.16-1.95 (m, 2H), 1.95-1.83 (m, 1H), 1.83-1.69 (m, 1H), 1.65-1.53 (m, 2H), 1.49 (s, 9H)。

step c:

to a stirred mixture of 4- [4, 5-dichloro-2- (prop-2-en-1-yloxy) benzoyl at room temperature]Azepane-1-carboxylic acid tert-butyl ester (0.60 g, 1.40 mmol) and (CS) (iii) -2-methylpropane-2-sulfinamide (0.34 g, 2.80 mmol) in THF (3 mL) Ti (OEt)₄(1.60 g, 7.00 mmol). The resulting solution was stirred at 70 ℃ for 16 hours under nitrogen atmosphere. The reaction was quenched with saturated NaHCO at room temperature₃Aqueous solution (50 mL) was quenched. The resulting mixture was extracted with EA (3X 50 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography, eluting with PE/EA (1/1), and obtaining 4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] in the form of pale yellow oil]([[(S) -2-methylpropan-2-sulfinyl]Imino radical]) Methyl radical]N-azacycloheptane-1-carboxylic acid tert-butyl ester (0.30 g, 32%): C₂₅H₃₆Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 531, 533 (3: 2), found 531, 533 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.18 (s, 1H), 6.98 (s, 1H), 6.14-5.89 (m, 1H), 5.47-5.26 (m, 2H), 4.62-4.51 (m, 2H), 3.69-3.42 (m, 2H), 3.42-3.15 (m, 2H), 2.73-2.31 (m, 2H), 2.23-2.08 (m, 1H), 2.05-1.68 (m, 2H), 1.67-1.51 (m, 2H), 1.50-1.46 (m, 9H), 1.23 (s, 9H)。

step d:

4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] stirred at-78 ℃ under nitrogen atmosphere ]([[(S) -2-methylpropan-2-sulfinyl]Imino radical]) Methyl radical]To a solution of t-butyl azepane-1-carboxylate (0.30 g, 0.56 mmol) in THF (5 mL) was added DIBALH (1.13 mL, 1.13 mmol, 1M in toluene) dropwise. The resulting mixture was stirred at-78 ℃ for 2 hours under nitrogen. The reaction was quenched with saturated NH at-78 deg.C₄Aqueous Cl (2 mL) was quenched. The resulting mixture was diluted with water (30 mL) and extracted with EA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. Purifying the residue by silica gel column chromatography, eluting with PE/EA (3/1), to obtain 4- [ (R) ((R) ()) as an off-white solidR) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]N-heptane-1-carboxylic acid tert-butyl ester (0.20 g, 53%): C₂₅H₃₈Cl₂N₂O₄S [M + H]⁺Calculated lcms (esi): 533, 535 (3: 2), found 533, 535 (3: 2);¹H NMR (400 MHz, CDCl₃) δ 7.26 (s, 1H), 6.95 (s, 1H), 6.09-5.95 (m, 1H), 5.46-5.32 (m, 2H), 4.67 (d, J = 31.6 Hz, 1H), 4.59-4.44 (m, 2H), 3.76-3.37 (m, 2H), 3.34-3.08 (m, 2H), 2.03-1.80 (m, 3H), 1.80-1.59 (m, 1H), 1.57-1.30 (m, 11H), 1.24-1.15 (m, 10H)。

step e:

4- [ (ii) to stirring at room temperatureR) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]To a solution of azepane-1-carboxylic acid tert-butyl ester (0.12 g, 0.23 mmol) in DCM (2 mL) was added TFA (0.5 mL). The resulting solution was stirred at room temperature for 30 minutes. The residue was taken up with saturated NaHCO ₃The aqueous solution was basified to pH 8. The resulting mixture was diluted with water (20 mL) and washed with waterEA (3X 30 mL). The combined organic layers were washed with brine (3X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give (a) as a pale yellow solidS)-N-[(R) -azepan-4-yl [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]2-methylpropane-2-sulfinamide (0.12 g, crude), which was used in the next step without further purification: c₂₀H₃₀Cl₂N₂O₂S [M + H]⁺Calculated lcms (esi): 433, 435 (3: 2), found 433, 435 (3: 2).

Step f:

stirring at room temperature (4)R) (2, 2-dimethyl-1, 3-dioxolane-4-carboxylic acid (81 mg, 0.55 mmol) and HATU (0.26 g, 0.69 mmol) in DMF (3 mL) was addedS)-N-[(R) -azepan-4-yl [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]Methyl radical]2-methylpropane-2-sulfinamide (0.12 g, 0.28 mmol) and Et₃N (83 mg, 0.82 mmol). The reaction was stirred at room temperature for 30 minutes. The resulting solution was quenched with water (50 mL) and extracted with EA (3X 40 mL). The combined organic layers were washed with brine (2X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with 63% aqueous ACN (plus 0.05% TFA) to give (a) as a pale yellow oil S)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Azepan-4-yl]) Methyl radical]2-methylpropane-2-sulfinamide (90 mg, 46%): C₂₆H₃₈Cl₂N₂O₅S [M + H]⁺Lcms (esi) calculated value of (a): 561, 563 (3: 2), found 561, 563 (3: 2).

Step g:

stirring at room temperature (S)-N-[(R) - [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl]([1-[(4R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Azepan-4-yl]) Methyl radical]-2-methylpropane-2-sulfinamide (90 mg, 0.16 mmol) and Pd (PPh)₃)₄ (2 mg, 0.002 mmol) in THF (2 mL) NaBH was added₄(18 mg, 0.48 mmol). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was washed with saturated NH₄Aqueous Cl (1 mL) was quenched and concentrated under reduced pressure to give (A) as a brown solidS)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) ([1- [ (4) ]R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Azepan-4-yl]) Methyl radical]-2-methylpropane-2-sulfinamide (90 mg, crude), which was used in the next step without further purification: c₂₃H₃₄Cl₂N₂O₅S [M + H]⁺Calculated lcms (esi): 521, 523 (3: 2), found 521, 523 (3: 2).

Step h:

stirring at room temperature (S)-N-[(R) - (4, 5-dichloro-2-hydroxyphenyl) ([1- [ (4) ] R) -2, 2-dimethyl-1, 3-dioxolane-4-carbonyl]Azepan-4-yl]) Methyl radical]To a mixture of (E) -2-methylpropane-2-sulfinamide (90 mg, 0.17 mmol) in 1, 4-dioxane (1 mL) was added aqueous HCl (4)N1.00 mL). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge Prep C18 OBD column, 5 μm, 19X 150 mm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 10% B to 29% B in 7 minutes; a detector: UV 220/254 nm; retention time: RT (reverse transcription)₁6.30 minutes; RT (reverse transcription)₂6.60 minutes.

The fractions containing the desired product were collected at 6.30 minutes and concentrated under reduced pressure to afford compound 333 ((2) as an off-white solidR)-1-[4-[(R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Azepan-1-yl]-2, 3-dihydroxypropan-1-one trifluoroacetic acid isomer 1) (10.3 mg, 12% of two steps in total): C₁₆H₂₂Cl₂N₂O₄ [M + H]⁺ Calculated lcms (esi): 377, 379 (3: 2), found 377, 379 (3: 2).¹H NMR (400 MHz, CD₃OD) δ 7.43 (d, J = 11.8 Hz, 1H), 7.08 (d, J = 6.5 Hz, 1H), 4.47 (dt, J = 26.7, 5.6 Hz, 1H), 4.22 (t, J = 8.9 Hz, 1H), 3.84-3.46 (m, 5H), 3.46-3.33 (m, 1H), 2.36-2.18 (m, 1H), 2.18-1.94 (m, 2H), 1.88-1.58 (m, 2H), 1.51-1.27 (m, 2H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -76.95.

Fractions containing the desired product were collected at 6.60 minutes and concentrated under reduced pressure to afford compound 334 ((2) as an off-white solidR)-1-[4-[(R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group ]Azepan-1-yl]-2, 3-dihydroxypropan-1-one trifluoroacetic acid isomer 2) (10.6 mg, 12% of the two steps total): C₁₆H₂₂Cl₂N₂O₄ [M + H]⁺ Lcms (esi) calculated value of (a): 377, 379 (3: 2), found 377, 379 (3: 2).¹H NMR (400 MHz, CD₃OD) δ 7.43 (s, 1H), 7.08 (d, J = 2.2 Hz, 1H), 4.50 (t, J = 5.4 Hz, 1H), 4.34-4.19 (m, 1H), 3.98-3.52 (m, 6H), 2.31-2.02 (m, 2H), 2.02-1.83 (m, 1H), 1.72-1.44 (m, 3H), 1.41-1.21 (m, 1H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -76.94.

Example 250 Compound 335 (, (2R,3S)-2-[4-[(R) -amino (5-chloro-2-hydroxy-4-methylphenyl) methyl]Piperidine-1-carbonyl]Oxetane-3-ol trifluoroacetic acid

Step a:

stirring at room temperature (2R,3S) (1) - (3-benzoyloxy) oxolane-2-carboxylic acid (0.12 g, 0.49 mmol) and HATU (0.19 g, 0.49 mmol) in DMF (3 mL) was addedS)-N-[(R) - [ 5-chloro-4-methyl-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]-2-methylpropane-2-sulfinamide (intermediate 25, example 25) (0.13 g, 0.33 mmol) and Et₃N (99 mg, 0.98 mmol). The reaction solution was stirred at room temperature for 0.5 hour. The resulting solution was quenched with water (50 mL) and extracted with EA (3X 40 mL). The combined organic layers were washed with brine (2X 30 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate is reducedAnd (5) concentrating under pressure. The residue was purified by reverse phase chromatography using a column chromatography column having 10 mmoL/L NH₄HCO₃Eluted with 55% ACN in water to give (A) as a pale yellow foam2R,3S)-2-[4-[(R) - [ 5-chloro-4-methyl-2- (prop-2-en-1-yloxy) phenyl]([ [ (S) -2-methylpropane-2-sulfinyl) ]Amino group]) Methyl radical]Piperidine-1-carbonyl]Oxetane-3-benzoic acid ester (0.13 g, 65%): C₃₂H₄₁ClN₂O₆S[M + H]⁺Lcms (esi) calculated value of (a): 617, 619 (3: 1), found 617, 619 (3: 1);¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, J = 7.6 Hz, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.70-7.53 (m, 1H), 7.53-7.37 (m, 2H), 7.11-7.01 (m, 1H), 6.70 (d, J = 22.3 Hz, 1H), 6.10 -5.92 (m, 1H), 5.88 (td, J = 6.1, 2.5 Hz, 1H), 5.45-5.23 (m, 2H), 4.92 (d, J =5.6 Hz, 1H), 4.72-4.37 (m, 4H), 4.37-4.28 (m, 1H), 4.10-3.96 (m, 1H), 3.81-3.71 (m, 1H), 3.05-2.67 (m, 1H), 2.46-2.29 (m, 4H), 2.29-2.12 (m, 1H), 1.99-1.81 (m, 1H), 1.76-1.54 (m, 1H), 1.52-1.38 (m, 1H), 1.25-1.17 (m, 3H), 1.11 (d, J = 29.8 Hz, 9H)

step b:

stirring at room temperature (2R,3S)-2-[4-[(R) - [ 5-chloro-4-methyl-2- (prop-2-en-1-yloxy) phenyl]([[(S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidine-1-carbonyl]Oxetane-3-benzoic acid ester (0.13 g, 0.21 mmol) and Pd (PPh)₃)₄ (5 mg, 0.004 mmol) in THF (3 mL) NaBH was added₄ (16 mg, 0.42 mmol). The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was washed with saturated NH₄Aqueous Cl (0.5 mL) was quenched and concentrated under reduced pressure to give (as a brown oil) ((R))2R,3S)-2-[4-[(R) - (5-chloro-2-hydroxy-4-methylphenyl) ([ ((ii) ((iii))S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidine-1-carbonyl]Oxetane-3-benzoate (0.12 g, crude), which was used in the next step without further purification: c₂₉H₃₇ClN₂O₆S[M + H]⁺Calculated lcms (esi): 577, 579 (3: 1), found 577, 579 (3: 1).

Step c:

stirring at room temperature (2R,3S)-2-[4-[(R) - (5-chloro-2-hydroxy-4-methylphenyl) ([ ((ii) ((iii))S) -2-methylpropan-2-sulfinyl]Amino group]) Methyl radical]Piperidine-1-carbonyl]To a solution of oxacyclopentane-3-benzoate (0.12 g, 0.21 mmol) in THF (2 mL) was added aqueous HCl (4) N1 mL). The reaction solution was stirred at room temperature for 1 hour and concentrated under reduced pressure to obtain (a) as a brown solid2R,3S)-2-[4-[(R) -amino (5-chloro-2-hydroxy-4-methylphenyl) methyl]Piperidine-1-carbonyl]Oxetane-3-benzoate (95 mg, crude), which was used in the next step without further purification: c₂₅H₂₉ClN₂O₅ [M + H]⁺Calculated lcms (esi): 473, 475 (3: 1), found 473, 475 (3: 1).

Step d:

at room temperature will: (2R,3S)-2-[4-[(R) -amino (5-chloro-2-hydroxy-4-methylphenyl) methyl]Piperidine-1-carbonyl]Oxetane-3-benzoate (95 mg, 0.20 mmol) was stirred in a solution of methylamine in methanol (4 mL) for 16 h. The reaction was concentrated under reduced pressure. The residue was dissolved in HCl (1)N30 mL). The aqueous layer was extracted with EA (2X 30 mL). The aqueous layer was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xselect CSH OBD column 30X 150 mm 5 μm; mobile phase a water (plus 0.05% TFA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: from 7% B to 20% B in 7 minutes; a detector: UV 254/220 nm; retention time: 6.93 minutes. The fractions containing the desired product were collected and concentrated under reduced pressure to give compound 335 as an off-white solid (, (R-C.) (I.))2R,3S)-2-[4-[(R) -amino (5-chloro-2-hydroxy-4-methylphenyl) methyl ]Piperidine-1-carbonyl]Oxetan-3-ol trifluoroacetic acid) (52.1 mg, 51% in total three)₁₈H₂₅ClN₂O₄ [M + H]⁺Lcms (esi) calculated value of (a): 369, 371 (3: 1), found 369, 371 (3: 1);¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 6.85 (s, 1H), 4.73-4.46 (m, 3H), 4.29-4.00 (m, 3H), 3.95-3.82 (m, 1H), 3.17-2.90 (m, 1H), 2.78-2.48 (m, 1H), 2.44-2.27 (m, 4H), 2.27-2.10 (m, 1H), 2.08-1.90 (m, 2H), 1.55-1.07 (m, 3H)； ¹⁹F NMR (376 MHz, CD₃OD) δ -77.07.

example 251 Compound 336 ((2)R)-1-[4-[(S) - (4, 5-dichloro-2-hydroxyphenyl) (methylamino) methyl]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one); compound 337 ((2)R)-1-[4-[(R) - (4, 5-dichloro-2-hydroxyphenyl) (methylamino) methyl]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one)

Step a:

separation by chiral preparative HPLC under the following conditions (2)R) -1- [4- [ (4, 5-dichloro-2-hydroxyphenyl) (methylamino) methyl]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one (free base of compound 196, example 188) (40 mg) column: chiralpak IF, 2 × 25 cm, 5 μm; mobile phase A: hexane (0.1% IPA), mobile phase B: EtOH; flow rate: 20 mL/min; gradient: from 30% B to 30% B in 18 minutes; a detector: UV 254/220 nm; retention time: RT (reverse transcription)₁10.21 minutes; RT (reverse transcription)₂14.65 minutes.

The faster eluting enantiomer was obtained as compound 337 ((2) as an off-white solid at 10.21 minR)-1-[4-[(R) - (4, 5-dichloro-2-hydroxyphenyl) (methylamino) methyl]Piperidin-1-yl radical]-2, 3-dihydroxypropan-1-one) (4 mg, 10%): C₁₆H₂₂Cl₂N₂O₄ [M + H]⁺Calculated lcms (esi): 377, 379 (3: 2), found 377, 379 (3: 2); ¹H NMR (400 MHz, CD₃OD) δ 7.44 (s, 1H), 7.11 (s, 1H), 4.71-4.31 (m, 2H), 4.31-4.03 (m, 2H), 3.85-3.51 (m, 2H), 3.25-2.98 (m, 1H), 2.84-2.36 (m, 2H), 2.58 (s, 3H), 2.15-1.9 (m, 1H), 1.54-1.01 (m, 3H)。

The slower eluting enantiomer was obtained as compound 336 ((2) as an off-white solid at 14.65 minR)-1-[4-[(S) - (4, 5-dichloro-2-hydroxyphenyl) (methylamino) methyl]Piperidin-1-yl]-2, 3-dihydroxypropan-1-one) (11 mg, 28%): C₁₆H₂₂ Cl₂N₂O₄ [M + H]⁺Lcms (esi) calculated value of (a): 377, 379 (3: 2), found 377, 379 (3: 2); ¹H NMR (400 MHz, CD₃OD) δ 7.17 (s, 1H), 6.87 (s, 1H), 4.65-4.44 (m, 2H), 4.13 (dd, J = 31.3, 13.6 Hz, 1H), 3.73-3.57 (m, 3H), 3.21-2.89 (m, 1H), 2.80-2.51 (m, 1H), 2.39 (s, 3H), 2.21-2.02 (m, 1H), 1.97 (d, J = 12.9 Hz, 1H), 1.55 (d, J = 13.0 Hz, 1H), 1.37-1.16 (m, 2H)。

example 252 Compound 338 (5- [4- [ (()R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]-1, 3-oxazinan-2-one isomer 1); compound 210 (5- [4- [ (()R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]-1, 3-oxazinan-2-one isomer 2)

Step a:

purification of 5- [4- [ (ii) by preparative chiral HPLC under the following conditionsR) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]-1, 3-oxazinan-2-one trifluoroacetic acid (compound 279, table 1b) (0.14 g, 0.27 mmol) column: CHIRALPAK IE, 2X 25 cm, 5 μm; mobile phase A: hexane (plus 0.2% IPA), mobile phase B: EtOH; flow rate: 15 mL/min; gradient: from 50% B to 505B in 23 minutes; a detector: UV 220/254 nm; retention time: RT (reverse transcription)₁15.37 minutes; RT (reverse transcription)₂19.03 minutes; injection volume 0.3 mL; the test times are 8.

The faster eluting enantiomer was obtained as compound 210 (5- [4- [) (in the form of an off-white solid at 15.37 minutes) R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]-1, 3-oxazinan-2-one isomer 2) (32.6 mg, 30%): C₁₇H₂₁Cl₂N₃O₄ [M + H]⁺Calculated lcms (esi): 402, 404 (3: 2), measured 402, 404 (3: 2);¹H NMR (400 MHz,CD₃OD) δ 7.23 (d, J = 7.2 Hz, 1H), 6.87 (s, 1H), 4.55 (dd, J = 41.0, 13.3 Hz, 1H), 4.42-4.24 (m, 2H), 4.10 (dd, J = 40.0, 13.8 Hz, 1H), 3.91 (dd, J = 13.5, 7.6 Hz, 1H), 3.54-3.36 (m, 3H), 3.18-2.97 (m, 1H), 2.60 (dt, J = 33.9, 12.8 Hz, 1H), 2.16-1.93 (m, 2H), 1.51 (dd, J =28.7, 13.3 Hz, 1H), 1.42-1.06 (m, 2H)。

the slower eluting enantiomer was obtained as compound 338 (5- [4- [ (R) ()) in the form of an off-white solid at 19.03 minutesR) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carbonyl]-1, 3-oxazinan-2-one isomer 1) (28.5 mg, 26%): C₁₇H₂₁Cl₂N₃O₄ [M + H]⁺Calculated lcms (esi): 402, 404 (3: 2), measured 402, 404 (3: 2);¹H NMR (400 MHz, CD₃OD) δ 7.24 (s, 1H), 6.87 (s, 1H), 4.55 (dd, J = 36.5, 13.4 Hz, 1H), 4.44-4.26 (m, 2H), 4.10 (dd, J = 36.6, 13.7 Hz, 1H), 3.91 (t, J = 7.3 Hz, 1H), 3.52-3.38 (m, 3H), 3.11 (dt, J = 41.2, 13.2 Hz, 1H), 2.70-2.49 (m, 1H), 2.11-1.94 (m, 2H), 1.51 (t, J = 16.2 Hz, 1H), 1.35-1.09 (m, 2H)。

EXAMPLE 253 Compound 78 (2- [ amino [1- (2-carbamoylethyl) piperidin-4-yl ] methyl ] -4, 5-dichlorophenyl formate);

step a:

under nitrogen atmosphere, at 120 ℃ willN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]A mixture of-2-methylpropane-2-sulfinamide (0.20 g, 0.48 mmol) in prop-2-enamide (3 mL) was stirred for 12 hours. The resulting mixture was diluted with EA (20 mL) and water (20 mL). The aqueous solution was extracted with EA (2X 20 mL). The combined organic layers were washed with brine (2X 20 mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 3- (4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl) as a yellow oil ][ (2-methylpropane-2-sulfinyl) amino group]Methyl radical]Piperidin-1-yl) propionamide (0.13 g, 56%); c₂₂H₃₃Cl₂N₃O₃S [M + H]⁺Lcms (esi) calculated value of (a): 490, 492 (3: 2) measured: 490, 492 (3: 2);¹H NMR (300 MHz, DMSO-d₆) δ 7.54 (s, 1H), 7.23 (s, 1H), 6.11-5.91 (m, 1H), 5.47-5.13 (m, 2H), 4.74-4.47 (m, 2H), 4.47-4.31 (m, 1H), 3.54-3.43 (m, 1H), 3.40-3.29 (m, 1H), 3.29-3.10 (m, 2H), 2.90-2.61 (m, 2H), 2.23-1.79 (m, 3H), 1.54-1.21 (m, 3H), 1.02-0.93 (m, 10H)。

step b:

to a stirred 3- (4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl group at room temperature][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]To a solution of piperidin-1-yl) propionamide (0.10 g, 0.20 mmol) in THF (4 mL) was added L-proline (47 mg, 0.41 mmol) and Pd (PPh)₃)₄(47 mg, 0.04 mmol). The resulting mixture was stirred at room temperature under nitrogen for 16 hours. The reaction was quenched with water (1 mL) at room temperature. The resulting mixture was concentrated under reduced pressure to give 3- [4- [ (4, 5-dichloro-2-hydroxyphenyl) [ (2-methylpropane-2-sulfinyl) amino group]Methyl radical]Piperidin-1-yl radical]Propionamide (0.10 g, crude), which was used in the next step without further purification: c₁₉H₂₉Cl₂N₃O₃S [M + H]⁺Calculated lcms (esi): 450, 452 (3: 2) found: 450, 452 (3: 2);

step c:

to a stirred mixture of 3- [4- [ (4, 5-dichloro-2-hydroxyphenyl) [ (2-methylpropane-2-sulfinyl) amino group at room temperature]Methyl radical]Piperidin-1-yl radical]To a solution of propionamide (0.10 g, 0.22 mmol) in dioxane (2 mL) was added HCl (4)N1 mL). The reaction was stirred at room temperature for 5 hours. The mixture was washed with saturated NaHCO ₃The aqueous solution was neutralized to pH = 7. The mixture was concentrated under reduced pressure.

The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC under the following conditions (Column: Xbridge C18 OBD Prep Column, 19 mm. times.250 mm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 4% B to 24% B in 8 minutes; 254/210 nm; Rt: 6.67 minutes.) fractions containing the desired product were collected and concentrated under reduced pressureCompound 78 (2- [ amino [1- (2-carbamoylethyl) piperidin-4-yl) is obtained as an off-white solid]Methyl radical]-4, 5-dichlorophenyl formate) (10 mg, 14% of the total of the two steps) C₁₅H₂₁Cl₂N₃O₂ [M + H]⁺Lcms (esi) calculated value of (a): 346, 348 (3: 2) found: 346, 348 (3: 2); ¹H NMR (300 MHz, CD₃OD) δ 7.19 (s, 1H), 6.85 (s, 1H), 3.89 (d, J = 7.8 Hz, 1H), 3.10-3.00 (m, 1H), 3.00-2.91 (m, 1H), 2.72-2.60 (m, 2H), 2.41 (t, J = 7.3 Hz, 2H), 2.14-1.86 (m, 3H), 1.86-1.73 (m, 1H), 1.51-1.18 (m, 3H)。

example 254 Compound 81 (4- [ (S))S) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carboxamide); compound 82 (4- [ (()R) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carboxamide

Step a:

at room temperature with stirringN- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl](piperidin-4-yl) methyl]2-methylpropane-2-sulfinamide (0.20 g, 0.48 mmol) and Et₃To a mixture of N (73 mg, 0.72 mmol) in DCM (2 mL) was added isocyanatotrimethylsilane (66 mg, 0.57 mmol). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluted with 70% aqueous ACN (0.05% TFA) to give 4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl ] oil as a yellow oil ][ (2-methylpropane-2-sulfinyl) amino group]Methyl radical]Piperidine-1-carboxamide (0.15 g, 68%); c₂₀H₂₉Cl₂N₃O₃S [M + H]⁺Calculated lcms (esi): 462, 464 (3: 2) found: 462, 464 (3: 2).

Step b:

to a stirred 4- [ [4, 5-dichloro-2- (prop-2-en-1-yloxy) phenyl group at room temperature][ (2-methylpropane-2-sulfinyl) amino]Methyl radical]Piperidine-1-carboxamide (0.15 g, 0.33 mmol) and Pd (PPh)₃)₄ (7 mg, 0.01 mmol) in THF (2 mL) NaBH was added₄(25 mg, 0.65 mmol). The reaction was stirred at room temperature for 1 hour. The reaction solution was saturated with NH₄Aqueous Cl (1 mL) was quenched and concentrated under reduced pressure to give 4- [ (4, 5-dichloro-2-hydroxyphenyl) [ (2-methylpropane-2-sulfinyl) amino ] as a brown solid]Methyl radical]Piperidine-1-carboxamide (0.13 g, crude), which was used directly in the subsequent step without further purification C₁₇H₂₅Cl₂N₃O₃S [M + H]⁺Calculated lcms (esi): measured values of 422, 424 (3: 2): 422, 424 (3: 2).

Step c:

to a stirred mixture of 4- [ (4, 5-dichloro-2-hydroxyphenyl) [ (2-methylpropane-2-sulfinyl) amino group at room temperature]Methyl radical]To a solution of piperidine-1-carboxamide (0.13 g, 0.31 mmol) in dioxane (2 mL) was added HCl (4)N1 mL). The reaction was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: xbridge C18 OBD Prep Column 100A, 10 μm, 19 mm × 250 mm; mobile phase A: having a NH concentration of 20 mmol/L ₄HCO₃Water, mobile phase B: ACN; flow rate: 25 mL/min; gradient: from 20% B to 80% B in 6.5 minutes; a detector: UV 254/210 nm; retention time: 5.95 minutes. The fractions containing the desired product were collected, concentrated under reduced pressure and afforded 4- [ amino (4, 5-dichloro-2-hydroxyphenyl) methyl as an off-white solid]Piperidine-1-carboxamide (69.6 mg, 67% two steps in total): C₁₃H₁₇Cl₂N₃O₂ [M + H]⁺Calculated lcms (esi): 318, 320 (3: 2) found: 318, 320 (3: 2); ¹H NMR (300 MHz, CD₃OD) δ 7.21 (s, 1H), 6.86 (s, 1H), 4.18-4.03 (m, 1H), 4.03-3.93 (m, 1H), 3.89 (d, J = 7.6 Hz, 1H), 2.86-2.62 (m, 2H), 2.10-1.85 (m, 2H), 1.50-1.34 (m, 1H), 1.34-1.12 (m, 2H)。

step d:

4- (amino (4, 5-dichloro-2-hydroxyphenyl) methyl) piperidine-1-carboxamide (65mg, 0.20 mmol) was isolated by preparative chiral HPLC under the following conditions: CHIRALPAK IG, 20X 250 mm, 5 μm;mobile phase A: hexane (plus 0.2% IPA) -HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL/min; gradient: from 30% B to 30% B in 15 minutes; a detector: UV 220/254 nm; retention time: RT (reverse transcription)₁9.17 minutes; RT (reverse transcription)₂12.55 minutes. The faster eluting enantiomer was obtained as compound 81 (4- [ (4- [)) in the form of an off-white solid at 9.17 minutesS) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carboxamide) (10 mg, 15%): C₁₃H₁₇Cl₂N₃O₂ [M + H]⁺Calculated lcms (esi): 318, 320 (3: 2) found: 318, 320 (3: 2); ¹H NMR (300 MHz, CD₃OD) δ 7.19 (s, 1H), 6.85 (s, 1H), 4.15-4.03 (m, 1H), 4.02-3.91 (m, 1H), 3.87 (d, J= 7.6 Hz, 1H), 2.85-2.66 (m, 2H), 2.04-1.84 (m, 2H), 1.50-1.32 (m, 1H), 1.32-1.07 (m, 2H). The slower eluting enantiomer was obtained as compound 82 (4- [ ((s) ()) in the form of an off-white solid at 12.55 minutesR) -amino (4, 5-dichloro-2-hydroxyphenyl) methyl group]Piperidine-1-carboxamide) (8 mg, 12%): C₁₃H₁₇Cl₂N₃O₂ [M + H]⁺Calculated lcms (esi): 318, 320 (3: 2) found: 318, 320 (3: 2);¹H NMR (300 MHz, CD₃OD) δ 7.21 (s, 1H), 6.86 (s, 1H), 4.16-4.06 (m, 1H), 4.02-3.93 (m, 1H), 3.89 (d, J = 7.6 Hz, 1H), 2.86-2.62 (m, 2H), 2.06-1.85 (m, 2H), 1.48-1.37 (m, 1H), 1.37-1.09 (m, 2H)。

example 255 evaluation of Kv1.3 Potassium channel blocker Activity

The tests described below were used to evaluate the activity of the disclosed compounds as kv1.3 potassium channel blockers.

Cell culture

CHO-K1 cells stably expressing Kv1.3 were grown in DMEM containing 10% heat-inactivated FBS, 1 mM sodium pyruvate, 2 mM L-glutamine and G418 (500 μ G/ml). At 37 ℃ in 5% CO₂Cells were grown in culture flasks in a humidified incubator.

Solutions of

The cells were bathed in an extracellular fluid containing 140 mM NaCl, 4 mM KCl, 2 mM CaCl₂、1 mM MgCl₂5 mM glucose, 10 mM HEPES; adjusting the pH value to 7.4 by NaOH; 295-305 mOsm. The inner solution contained 50 mM KCl, 10 mM NaCl, 60 mM KF, 20 mM EGTA, 10 mM HEPES; the pH was adjusted to 7.2 with KOH; 285 mOsm. All compounds were dissolved in DMSO at 30 mM. The compound stock solution was diluted fresh with external solution to concentrations of 30 nM, 100 nM, 300 nM, 1 μ M, 3 μ M, 10 μ M, 30 μ M and 100 μ M. The highest content of DMSO (0.3%) was present at 100 μ M.

Voltage scheme

The current induced by applying a 100 ms depolarization pulse from-90 mV (holding potential) to +40 mV was applied at a frequency of 0.1 Hz. The control (no compound) and compound pulse sequences applied for each compound concentration contained 20 pulses. A 10 second break was used between pulse trains (see table a below).

Table a. voltage scheme

Patch clamp recording and composite applications

Whole-cell current recording and compound application was enabled by means of an automatic patch clamp platform patchliner (nanion Technologies gmbh). EPC 10 patch clamp amplifier (HEKA Elektronik Dr. Schulze GmbH) was used with Patchmaster software (HEKA Elektronik Dr. Schulze GmbH) for data acquisition. The data was sampled at 10kHz without filtering. The Passive leakage current (Passive leak currents) was subtracted online using the P/4 program (HEKA Elektronik Dr. Schulze GmbH). The same cells were continuously subjected to increasing concentrations of the compounds without rinsing. The total compound incubation time before the subsequent pulse sequence was no longer than 10 seconds. Peak current suppression was observed during compound equilibration.

Data analysis

AUC and peak values were obtained with PatchMaster (HEKA Elektronik Dr. Schulze GmbH). To measure IC ₅₀The last single pulse in the pulse sequence corresponding to a given compound concentration is used. AUC and Peak values obtained in the Presence of CompoundControl values in the absence of compound were normalized. Using origin (OridiLab), IC₅₀From data fitting the Hill equation: i is_{Compound (I)}/I_Control= (100-a)/(1 + ([ compound)]/IC₅₀) nH) + A, where IC₅₀The value is the concentration at which the current is suppressed to half maximum, [ compound ]]Is the concentration of compound applied, a is the fraction of unblocked current, and nH is the Hill coefficient.

Example 256 evaluation of hERG Activity

hERG electrophysiology

This assay is used to evaluate the inhibitory activity of the disclosed compounds on the hERG channel.

Cell culture

CHO-K1 cells stably expressing hERG were grown in Ham's F-12 medium with glutamine, 10% heat-inactivated FBS, 1% penicillin/streptomycin, hygromycin (100. mu.G/ml) and G418 (100. mu.G/ml). At 37 ℃ in 5% CO₂Cells were grown in culture flasks in a humidified incubator.

Solutions of

The cells were bathed in an extracellular fluid containing 140 mM NaCl, 4 mM KCl, 2 mM CaCl₂、1 mM MgCl₂5 mM glucose, 10 mM HEPES; adjusting the pH value to 7.4 by NaOH; 295-305 mOsm. The inner solution contained 50 mM KCl, 10 mM NaCl, 60 mM KF, 20 mM EGTA, 10 mM HEPES; the pH was adjusted to 7.2 with KOH; 285 mOsm. All compounds were dissolved in DMSO at 30 mM. The compound stock solution was diluted fresh with external solution to concentrations of 30 nM, 100 nM, 300 nM, 1 μ M, 3 μ M, 10 μ M, 30 μ M and 100 μ M. The highest content of DMSO (0.3%) was present at 100 μ M.

Voltage scheme

The voltage protocol (see table B) was designed to simulate voltage changes during cardiac action potentials with 300 ms depolarization to +20 mV (similar to the plateau phase of cardiac action potentials), 300 ms repolarization to-50 mV (induced tail currents), and the final step to a holding potential of-80 mV. The pulse frequency was 0.3 Hz. The control (no compound) and compound pulse sequences applied for each compound concentration contained 70 pulses.

Table b. hERG voltage protocol

Patch clamp recording and composite applications

Whole cell current recording and compound application was enabled by means of an automated patch clamp platform patchliner (nanion). EPC 10 patch clamp Amplifier (HEKA) was used with Patchmaster software (HEKA Elektronik Dr. Schulze GmbH) for data acquisition. The data was sampled at 10 kHz without filtering. The same cells were continuously subjected to increasing concentrations of the compounds without rinsing.

Data analysis

AUC and peak values were obtained with PatchMaster (HEKA Elektronik Dr. Schulze GmbH). To measure IC₅₀The last single pulse in the pulse sequence corresponding to a given compound concentration is used. AUC and peak values obtained in the presence of compound were normalized to control values in the absence of compound. Using origin (OridiLab), IC ₅₀From data fitting the Hill equation: i is_{Compound (I)}/I_Control= (100-a)/(1 + ([ compound)]/IC₅₀) nH) + A, where IC₅₀Is the concentration at which the current is suppressed to half maximum, [ Compound ]]Is the concentration of compound applied, a is the fraction of unblocked current, and nH is the Hill coefficient.

Table 1 provides a summary of the inhibitory activity of certain selected compounds on kv1.3 potassium channel and hERG channel.

TABLE 1 IC of certain exemplary Compounds for Kv1.3 Potassium channel and hERG channel₅₀Value (. mu.M).

Left untested.

Claims (78)

1. A compound of formula I or a pharmaceutically acceptable salt thereof,

；

wherein

Z is OR_a、NR_aR_bOr NR_b(C=O)R_a；

X₁Is H, halogen, CN, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, or halocycloalkyl;

X₂is H, halogen, CN, alkyl, haloalkyl, cycloalkyl or halocycloalkyl;

X₃is H, halogen, fluoroalkyl or alkyl;

or X₁And X₂Together with the carbon atom to which they are attached form an optionally substituted 6-membered aryl group;

or X₂And X₃Together with the carbon atom to which they are attached form an optionally substituted 6-membered aryl group;

R₃is H, halogen or alkyl;

or X₁And R₃Together with the carbon atom to which they are attached form an optionally substituted 6-membered aryl group;

R₁and R₂Each independently is H, alkyl, (CR) ₆R₇)_n4OR_a、(CR₆R₇)_n4NR_aR_b、(CR₆R₇)_n4NR_a(C=O)R_b、(CR₆R₇)_n4NR_aSO₂R_bOr (CR)₆R₇)_n4CONR_aR_b(ii) a Or R₁、R₂Together with the carbon atom to which they are attached form a 3-5 membered carbocyclic ring;

R₄is H, alkyl, haloalkyl, optionally substituted cycloalkyl, (CR)₆R₇)_n4OR_c、(CR₆R₇)_n4(C=O)R_c、(C=O)(CR₆R₇)_n4R_c、(CR₆R₇)_n4COOR_c、(CR₆R₇)_n4NR_c(C=O)R_d、(CR₆R₇)_n4(C=O)NR_cR_d、(C=O)(CR₆R₇)_n4NR_cR_d、(CR₆R₇)_n4(C=O)(C=O)NR_cR_d、(C=O)(CR₆R₇)_n4OR_c、(CR₆R₇)_n4SO₂R_c、(CR₆R₇)_n4SO₂NR_cR_dOptionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted-alkyl-aryl, optionally substituted-alkyl-heteroaryl, optionally substituted-alkyl-heterocycle, optionally substituted-alkyl-cycloalkyl or optionally substituted-cycloalkyl-alkyl;

R₅each occurrence of (a) is independently H, alkyl, cycloalkyl or oxo;

or two R₅The groups, together with the carbon atom to which they are attached, form a 3-7 membered optionally substituted saturated carbocyclic ring;

or two R₅The groups are attached to different carbon atoms on the carbocyclic ring and together form a bond or an alkyl chain containing 1-3 carbons;

R₆and R₇Each occurrence of (a) is independently H, alkyl, or cycloalkyl;

R_aand R_bEach occurrence of (a) is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl, or heteroaryl; or R_aAnd R_bTogether with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring comprising the nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S;

R_cand R_dEach occurrence of (A) is independently H, alkyl, substituted with 1-4 independently of each other halogen, OR ₈Or N (R)₈)₂Substituted alkyl, alkenyl, optionally substituted cycloalkyl, optionally substituted bicycloalkyl, optionally substituted spiroalkyl, optionally substituted saturated heteroA ring, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted-alkyl-aryl, an optionally substituted-alkyl-heteroaryl, an optionally substituted-alkyl-heterocycle, an optionally substituted-alkyl-cycloalkyl, or an optionally substituted-cycloalkyl-alkyl; or R_cAnd R_dTogether with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring containing the nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S;

R₈each occurrence of (a) is independently H, alkyl or optionally substituted heterocycle; or two R₈The groups together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring comprising the nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S;

R₉is H, alkyl, halogen or (CR)₆R₇)_n4OR_b；

Where valency permits, X₁、X₂、X₃、R₁、R₂、R₃、R₄、R₅、R₆、R₇、R₉、R_a、R_b、R_cAnd R_dThe alkyl, cycloalkyl, spiroalkyl, bicycloalkyl, heterocycle, aryl and heteroaryl groups in (a) are optionally substituted as applicable by 1 to 4 substituents each independently selected from alkyl, cycloalkyl, halocycloalkyl, haloalkyl, halogen, CN, - (CH) ₂)_0-2OR₈、N(R₈)₂、(C=O)C_1-4Alkyl, (C = O) N (R)₈)₂And oxo;

where the compound permits, n₁Each occurrence of (a) is independently an integer from 0 to 3;

n₂and n₃Each occurrence of (a) is independently an integer from 0 to 2; and

n₄each occurrence of (a) is independently an integer from 0 to 3.

2. The compound of claim 1, wherein n₂And n₃Independently for each occurrence of (a) is 0-1Is an integer of (1).

3. The compound of claim 1, wherein the structural motif

Has the advantages of

Or

The structure of (1).

4. The compound of claim 1, wherein the structural motif

Has the advantages of

Or

The structure of (1).

5. The compound of claim 1, wherein the structural motif

Has the advantages of

The structure of (1).

6. A compound according to any one of the preceding claims, wherein R₁And R₂Is H or alkyl.

7. The compound of any one of claims 1-5, which isIn R₁And R₂At least one occurrence of (CR)₆R₇)_n4OR_a、(CR₆R₇)_n4NR_aR_b、(CR₆R₇)_n4NR_a(C=O)R_b、(CR₆R₇)_n4NR_aSO₂R_bOr (CR)₆R₇)_n4CONR_aR_b。

8. The compound of claim 7, wherein R₁And R₂At least one occurrence of (A) is OR_aOr NR_aR_b。

9. The compound of any one of claims 1-5, wherein R₁、R₂Together with the carbon atoms to which they are attached form a 3-5 membered carbocyclic ring.

10. The compound of any one of claims 1-5, wherein R ₁And R₂Each independently of the other is H, Me, OH, CH₂OH、NH₂、NHMe、NMe₂、CH₂NH₂、CONH₂、CONHMe₂、CONMe₂、NH(C=O)Me、NMe(C=O)Me、

。

11. A compound according to any one of the preceding claims, wherein R₄Is H, alkyl, haloalkyl or cycloalkyl.

12. The compound of claim 11, wherein R₄Is H, Me or fluoroethyl.

13. Root of herbaceous plantThe compound of any one of claims 1-10, wherein R₄Is (CR)₆R₇)_n4OR_c、(CR₆R₇)_n4COR_c、(C=O)(CR₆R₇)_n4R_c、(CR₆R₇)_n4COOR_c、(CR₆R₇)_n4NR_c(C=O)R_d、(CR₆R₇)_n4(C=O)NR_cR_d、(CR₆R₇)_n4(C=O)(C=O)NR_cR_d、(C=O)(CR₆R₇)_n4OR_c、(CR₆R₇)_n4SO₂R_cOr (CR)₆R₇)_n4SO₂NR_cR_d。

14. The compound of claim 13, wherein R₄Is (CR)₆R₇)₂OR_c、(C=O)R_c、(C=O)(CR₆R₇)_1-2R_c、COOR_c、(CR₆R₇)_1-2NR_c(C=O)R_d、(C=O)NR_cR_d、(CR₆R₇)_n4(C=O)(C=O)NR_cR_d、(C=O)(CR₆R₇)_1-2OR_c、SO₂R_cOr SO₂NR_cR_d。

15. The compound of claim 14, wherein R₄Is (CH)₂)₂OH、(CH₂)₂OMe、(C=O)H、(C=O)Me、(C=O)CH₂OH、(C=O)CH₂OMe, (C = O) Et, (C = O) Ph, (C = O) isopropyl, (C = O) NH₂、(C=O)NHMe、(C=O)NMe₂、(C=O)CH₂NH₂、(C=O)CH₂NHMe、(C=O)CH(OH)CH₂OH、(C=O)CH(OMe)CH₂OH、(C=O)CH(OH)CH₂OMe、(C=O)(C=O)NMe₂、(C=O)OMe、SO₂Me、SO₂Et、SO₂CH₂OH、SO₂CH₂OMe、SO₂NH₂、SO₂NHMe or SO₂NMe₂。

16. The compound of claim 14, wherein R₄Is (C = O) R_c、(C=O)(CR₆R₇)_1-2R_c、(C=O)(CR₆R₇)_1-2OR_cOr SO₂R_c(ii) a And wherein R_cSelected from H, alkyl, by being each independently selected from halogen, OR₈And N (R)₈)₂Alkyl substituted with 1 to 4 substituents of (1-4), alkenyl, optionally substituted cycloalkyl, optionally substituted bicycloalkyl, optionally substituted spiroalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted-alkyl-aryl, optionally substituted-alkyl-heteroaryl, optionally substituted-alkyl-heterocycle, optionally substituted-alkyl-cycloalkyl, and optionally substituted-cycloalkyl-alkyl.

17. The compound of claim 14, wherein R_cOr R_dIs H, Me, Et,

、

、

。

18. The compound of claim 14, wherein R_cOr R_dIs a heterocycle selected from:

(ii) a Wherein the heterocycle is optionally substituted, where valence permits, with one or more cyano, cycloalkyl, fluoroalkyl, fluorocycloalkyl, halogen, OH, NH₂Oxo or (C = O) C_1-4Alkyl substitution.

19. The compound of claim 14, wherein R, where valence allows_cIs cycloalkyl, spiroalkyl or bicycloalkyl, each optionally substituted with 1-4 substituents, each independently selected from alkyl, halogen, CN, - (CH)₂)_0-2OR₈、N(R₈)₂、(C=O)N(R₈)₂And oxo.

20. The compound of claim 19, wherein R, where valence allows_cAre each optionally substituted by 1 to 4 substituents

Each of said substituents being independently selected from alkyl, halogen, CN, - (CH)₂)_0-2OR₈、N(R₈)₂、(C=O)N(R₈)₂And oxo.

21. The compound of any one of claims 1-10, wherein R₄Is optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted-alkyl-aryl, optionally substituted-alkyl-heteroaryl, optionally substituted-alkyl-heterocycle, optionally substituted cycloalkyl, optionally substituted-alkyl-cycloalkyl or optionally substituted-cycloalkyl-alkyl.

22. The compound of claim 21, wherein R₄Is a heterocycle selected from:

(ii) a Wherein the heterocycle is optionally substituted, where valence permits, with one or more cyano, cycloalkyl, fluoroalkyl, fluorocycloalkyl, halogen, OH, NH₂Oxo or (C = O) C_1-4Alkyl substitution.

23. The compound of claim 21, wherein R, where valence allows₄Is cycloalkyl optionally substituted with 1-4 substituents each independently selected from alkyl, halogen, CN, - (CH)₂)_0-2OR₈、N(R₈)₂、(C=O)N(R₈)₂And oxo.

24. The compound of claim 23, wherein R, where valence allows₄Are each optionally substituted by 1 to 4 substituents

Each of said substituents being independently selected from alkyl, halogen, CN, - (CH)₂)_0-2OR₈、N(R₈)₂、(C=O)N(R₈)₂And oxo.

25. The compound of any one of claims 1-10, wherein R₄Is that

Or a tautomer thereof.

26. The compound of any one of claims 1-25, wherein R₅Is H, alkyl or cycloalkyl.

27. The compound of any one of claims 1-25, wherein R₅Is oxo.

28. The compound of any one of claims 1-25, wherein two R ₅The groups are attached to different carbon atoms on the carbocyclic ring and together form a bond or an alkyl chain containing 1-3 carbons.

29. The compound of any one of claims 1-25, wherein two R are₅The groups together with the carbon atoms to which they are attached form a 3-7 membered optionally substituted saturated carbocyclic ring.

30. A compound according to any one of the preceding claims, wherein R_aAnd R_bAt least one of (a) is independently H, alkyl, cycloalkyl, saturated heterocycle, aryl or heteroaryl.

31. The compound of any one of claims 1-29, wherein R_aAnd R_bTogether with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring containing the nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S.

32. A compound according to any one of the preceding claims, wherein R₆And R₇Each occurrence of (a) is independently H or alkyl.

33. A compound according to any one of the preceding claims, wherein R₉Is H, alkyl or halogen.

34. The compound of any one of claims 1-32, wherein R₉Is (CR)₆R₇)_n4OR_b。

35. The compound of any one of claims 1-32, wherein R₉Is H, F or OH。

36. The compound of any one of the preceding claims, wherein Z is OR _a、NR_aR_bOr NR_b(C=O)R_a。

37. The compound of claim 36, wherein Z is OH, OMe, NH₂NHMe or NMe₂。

38. The compound of claim 36, wherein Z is OH.

39. A compound according to any one of the preceding claims, wherein X₁Is H, halogen, fluoroalkyl or alkyl.

40. A compound according to any one of the preceding claims, wherein X₁Is H, F, Cl, Br, Me, CF₃Or CF₂Cl。

41. The compound of claim 39, wherein X₁Is Me or Cl.

42. A compound according to any one of the preceding claims, wherein X₂Is H, halogen, fluoroalkyl or alkyl.

43. The compound of claim 42, wherein X₂Is H, F, Cl, Br, Me, CF₃Or CF₂Cl。

44. The compound of claim 42, wherein X₂Is Cl.

45. A compound according to any one of the preceding claims, wherein X₃Is H, F, Cl, Br, fluoroalkyl or alkyl.

46. Root of herbaceous plantThe compound of claim 45, wherein X₃Is H, F, Cl or CF₃。

47. The compound of any one of claims 1-35, wherein the moiety

Having each of the radicals represented by R₃Substituted by

The structure of (1).

48. The compound of any one of claims 1-47, wherein R ₃Is H or alkyl.

49. The compound of any one of claims 1-47, wherein R₃Is a halogen.

50. The compound of any one of claims 1-38, wherein the compound has the structure of formula II,

；

R_3'each occurrence of (a) is independently H, halogen, or alkyl; and

n₆is an integer of 0 to 2.

51. A compound according to claim 50, wherein R_3’Is H or alkyl.

52. A compound according to claim 50, wherein R_3’Is halogen.

53. A compound according to any one of the preceding claims, wherein R₈Is H, alkyl or an optionally substituted heterocycle.

54. A compound according to claim 53, wherein R₈Is H, Me, Et, Pr, Bu or a heterocycle selected from:

(ii) a Wherein the heterocycle is optionally substituted, where valence permits, with one or more cyano, cycloalkyl, fluoroalkyl, fluorocycloalkyl, halogen, OH, NH₂Oxo or (C = O) C_1-4Alkyl substitution.

55. The compound of any one of claims 1-52, wherein two R₈The groups, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclic ring comprising the nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S.

56. A compound according to any preceding claim, whereinn₁Is 0, 1, 2 or 3.

57. The compound of any one of claims 1-5, wherein n is₄Is 0, 1 or 2.

58. The compound of any one of claims 1-5, wherein R_cOr R_dIs independently H, alkyl, is independently selected from halogen, OR₈And N (R)₈)₂Alkyl, alkenyl, optionally substituted cycloalkyl, optionally substituted bicycloalkyl, optionally substituted spiroalkyl, optionally substituted saturated heterocycle, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted-alkyl-aryl, optionally substituted-alkyl-heteroaryl, optionally substituted-alkyl-heterocycle, optionally substituted-alkyl-cycloalkyl or optionally substituted-cycloalkyl-alkyl in the presence of 1 to 4 substituents of (a).

59. The compound of any one of claims 1-5, wherein R_cAnd R_dTogether with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring containing the nitrogen atom and 0-3 additional heteroatoms each selected from N, O and S.

60. The compound of any one of claims 1-5, wherein R _cOr R_dIs independently H, Me, Et,

。

61. the method of any one of claims 1-5Wherein R is_cOr R_dIs independently a heterocycle selected from:

(ii) a Wherein the heterocycle is optionally substituted, where valence permits, with one or more cyano, cycloalkyl, fluoroalkyl, fluorocycloalkyl, halogen, OH, NH₂Oxo or (C = O) C_1-4Alkyl substitution.

62. The compound of any one of claims 1-5, wherein R, where valence allows_cOr R_dIs cycloalkyl, spiroalkyl or bicycloalkyl, each optionally substituted with 1-4 substituents, each independently selected from alkyl, halogen, CN, - (CH)₂)_0-2OR₈、N(R₈)₂、(C=O)N(R₈)₂And oxo.

63. The compound of any one of claims 1-5, wherein R, where valence allows_cOr R_dIndependently of each other being optionally substituted by 1 to 4 substituents

Each of said substituents being independently selected from alkyl, halogen, CN, - (CH)₂)_0-2OR₈、N(R₈)₂、(C=O)N(R₈)₂And oxo.

64. The compound of claim 1, wherein the compound is selected from compounds 1-338 in table 1.

65. A pharmaceutical composition comprising at least one compound of any one of claims 1-64, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

66. A method of treating a condition in a mammalian species in need thereof, comprising administering to the mammalian species a therapeutically effective amount of at least one compound of any one of claims 1-64, or a pharmaceutically acceptable salt thereof, wherein the condition is selected from the group consisting of cancer, an immune disorder, a Central Nervous System (CNS) disorder, an inflammatory disorder, a gastrointestinal disorder, a metabolic disorder, a cardiovascular disorder, and a renal disorder.

67. The method of claim 66, wherein the immune disorder is transplant rejection or an autoimmune disease.

68. The method of claim 67, wherein the autoimmune disease is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, or type I diabetes.

69. The method of claim 66, wherein the Central Nervous System (CNS) disorder is Alzheimer's disease.

70. The method of claim 66, wherein the inflammatory disorder is an inflammatory skin condition, arthritis, psoriasis, spondylitis, periodontitis, or an inflammatory neuropathy.

71. The method of claim 66, wherein the gastrointestinal disorder is inflammatory bowel disease.

72. The method of claim 66, wherein the metabolic disorder is obesity or type II diabetes.

73. The method of claim 66, wherein the cardiovascular disorder is ischemic stroke.

74. The method of claim 66, wherein the kidney disease is chronic kidney disease, nephritis, or chronic renal failure.

75. The method of claim 66, wherein the condition is selected from the group consisting of cancer, transplant rejection, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, type I diabetes, Alzheimer's disease, inflammatory skin conditions, inflammatory neuropathy, psoriasis, spondylitis, periodontitis, Crohn's disease, ulcerative colitis, obesity, type II diabetes, ischemic stroke, chronic kidney disease, nephritis, chronic renal failure, and combinations thereof.

76. The method of claim 66, wherein the mammalian species is human.

77. A method of blocking Kv1.3 potassium channels in a mammalian species in need thereof, comprising administering to the mammalian species a therapeutically effective amount of at least one compound of any one of claims 1-64, or a pharmaceutically acceptable salt thereof.

78. The method of claim 76, wherein the mammalian species is human.